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METHOD OF TREATING OR AMELIORATING METABOLIC DISORDERS USING
BINDING PROTEINS FOR GASTRIC INHIBITORY PEPTIDE RECEPTOR (GIPR)
IN COMBINATION WITH GLP-1 AGONISTS
FIELD OF THE INVENTION
[0001] The present disclosure relates to the treatment or amelioration of a
metabolic disorder,
such as type 2 diabetes, elevated glucose levels, elevated insulin levels,
obesity, non-
alcoholic fatty liver disease, or cardiovascular diseases, using an antigen
binding protein
specific for the gastric inhibitory peptide receptor (GIPR).
BACKGROUND OF THE INVENTION
[0002] Glucose-dependent insulinotropic polypeptide (GIP) is a single 42-amino
acid peptide
secreted from K-cells in the small intestine (duodenum and jejunum). Human GIP
is derived
from the processing of proGIP, a 153-amino acid precursor that is encoded by a
gene
localized to chromosome 17q (Inagaki et al., Mol Endocrinol 1989; 3:1014-1021;
Fehmann et
al. Endocr Rev. 1995; 16:390-410). GIP was formerly called gastric inhibitory
polypeptide.
[0003] GIP secretion is induced by food ingestion. GIP has a number of
physiological effects
in tissues, including promotion of fat storage in adipocytes and promotion of
pancreatic islet
13-cell function and glucose-dependent insulin secretion. GIP and glucagon
like polypeptide-1
(GLP-1) are known insulinotropic factors ("incretins"). Intact GIP is rapidly
degraded by
DPPIV to an inactive form. The insulinotropic effect of GIP is lost in type 2
diabetic patients
while GLP-1's incretin effect remains intact (Nauck et al. J. Clinc. Invest.
1993; 91:301-307).
[0004] The GIP receptor (GIPR) is a member of the secretin-glucagon family of
G-protein
coupled receptors (GPCRs) having an extracellular N-terminus, seven
transmembrane
domains and an intracellular C-terminus. The N-terminal extracellular domains
of this family
of receptors are usually glycosylated and form the recognition and binding
domain of the
receptor. GIPR is highly expressed in a number of tissues, including the
pancreas, gut,
adipose tissue, heart, pituitary, adrenal cortex, and brain (Usdin et al.,
Endocrinology. 1993,
133:2861-2870). Human GIPR comprises 466 amino acids and is encoded by a gene
located
on chromosome 19q13.3 (Gremlich et al., Diabetes. 1995; 44:1202-8; Volz et
al., FEBS Lett.
1995, 373:23-29). Studies have suggested that alternative mRNA splicing
results in the
production of GIP receptor variants of differing lengths in human, rat and
mouse.
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[0005] GIPR knockout mice (Gipr 4-) are resistant to high fat diet-induced
weight gain and
have improved insulin sfensitivity and lipid profiles. (Yamada et al.,
Diabetes. 2006, 55:S86;
Miyawaki et al. Nature Med. 2002, 8:738-742). In addition, a novel small
molecule GIPR
antagonist SKL-14959 prevents obesity and insulin resistance. (Diabetologia
2008, 51:S373,
44th EASD Annual meeting poster).
[0006] Glucagon-like peptide-1 ("GLP-1") is a 31-amino acid peptide derived
from the
proglucagon gene. It is secreted by intestinal L-cells and released in
response to food
ingestion to induce insulin secretion from pancreatic f3 - cells (Diabetes
2004, 53:S3, 205-
214). In addition to the incretin effects, GLP-1 also decreases glucagon
secretion, delays
gastric emptying and reduces caloric intake (Diabetes Care, 2003, 26(10): 2929-
2940). GLP-
1 exerts its effects by activation of the GLP-1 receptor, which belongs to a
class B G-protein-
coupled receptor (Endocrinology. 1993, 133(4):1907-10). The function of GLP-1
is limited
by rapid degradation by the DPP-IV enzyme, resulting in a half-life of
approximately 2
minutes. Recently, long-lasting GLP-1 receptor agonists such as exenatide,
liraglutide,
dulaglutide have been developed and are now being used clinically to improve
glycemic
control in patients with type 2 diabetes. Furthermore, GLP-1 receptor agonists
also promote
body weight reduction as well as reduction in blood pressure and plasma
cholesterol levels in
patients (Bioorg. Med. Chem.Lett 2013, 23:4011-4018).
[0007] Collectively, these links to obesity and insulin resistance imply GIPR
inhibition is a
useful approach for therapeutic intervention, both as a monotherapy and in
combination with
GLP-1.
SUMMARY OF THE INVENTION
[0008] In one aspect, the present disclosure provides a method of treating a
subject with a
metabolic disorder, the method comprising administering to the subject a
therapeutically
effective amount of an antigen binding protein that specifically binds to a
protein having an
amino acid sequence having at least 90% amino acid sequence identity to an
amino acid
sequence of a GIPR. In one aspect the present invention is directed to a
method of treating a
subject with a metabolic disorder, the method comprising administering to the
subject a
therapeutically effective amount of a GLP-1 receptor agonist and a
therapeutically effective
amount of a GIPR antagonist that specifically binds to a protein having an
amino acid
sequence having at least 90% amino acid sequence identity to an amino acid
sequence of a
GIPR. In one embodiment, the metabolic disorder is a disorder of glucose
metabolism. In
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another embodiment, the glucose metabolism disorder comprises hyperglycemia
and
administering the antigen binding protein reduces plasma glucose. In another
embodiment,
the glucose metabolism disorder comprises hyperinsulinemia and administering
the antigen
binding protein reduces plasma insulin. In another embodiment, the glucose
metabolism
disorder comprises glucose intolerance and administering the antigen binding
protein reduces
increases glucose tolerance. In another embodiment, the glucose metabolism
disorder
comprises insulin resistance and administering the antigen binding protein
reduces insulin
resistance. In another embodiment, the glucose metabolism disorder comprises
diabetes
mellitus. In another embodiment, the subject is obese. In another embodiment,
administering
the antigen binding protein reduces body weight in an obese subject. In
another embodiment,
administering the antigen binding protein reduces body weight gain in an obese
subject. In
another embodiment, administering the antigen binding protein reduces fat mass
in an obese
subject. In another embodiment, the glucose metabolism disorder comprises
insulin resistance
and administering the antigen binding protein reduces insulin resistance in an
obese subject.
In another embodiment, administering the antigen binding protein reduces liver
steatosis in
an obese subject having increased liver steatosis. In another embodiment,
administering the
antigen binding protein reduces liver fat content in an obese subject having
increased liver fat
content.
[0009] In one aspect the present invention is directed to a method of
treatment comprising
administering to a subject a therapeutically effective amount of at least one
GLP-1 receptor
agonist in combination with administration of at least one GIPR antagonist
which upon
administration to a subject with symptoms of a metabolic disorder provides
sustained
beneficial effects.
[0010] In one embodiment, administration of at least one GLP-1 receptor
agonist in
combination with administration of at least one GIPR antagonist provides
sustained
beneficial effects of at least one symptom of a metabolic disorder.
[0011] In one embodiment, the therapeutically effective amounts of the GLP-1
receptor
agonist and the GIPR antagonist are combined prior to administration to the
subject.
[0012] In one embodiment, the therapeutically effective amounts of the GLP-1
receptor
agonist and the GIPR antagonist are administered to the subject sequentially.
[0013] In one embodiment, the therapeutically effective amounts of a GLP-1
receptor agonist
and a GIPR antagonist are synergistically effective amounts.
[0014] In one embodiment, the molar ratio of a GLP-1 receptor agonist to a
GIPR antagonist
is from about 1:1 to 1:110, 1:1 to 1:100, 1:1 to 1:75, 1:1 to 1:50, 1:1 to
1:25, 1:1 to 1:10, 1:1
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to 1:5, and 1:1. In one embodiment, the molar ratio of a GIPR antagonist to a
GLP-1 receptor
agonist is from about 1:1 to 1:110, 1:1 to 1:100, 1:1 to 1:75, 1:1 to 1:50,
1:1 to 1:25, 1:1 to
1:10, and 1:1 to 1:5.
[0015] In one embodiment, the GLP-1 receptor agonist is used in combination
with the GIPR
antagonist at therapeutically effective molar ratios of between about 1:1.5 to
1:150,
preferably 1:2 to 1:50.
[0016] In one embodiment, the GLP-1 receptor agonist and the GIPR antagonist
are present
in doses that are at least about 1.1 to 1.4, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, or
10 fold lower than the
doses of each compound alone required to treat a condition and/or disease.
[0017] In one embodiment, the GLP-1 receptor agonist is GLP-1(7-37) or a GLP-
1(7-37)
analog.
[0018] In one embodiment, the GLP-1 receptor agonist is selected from the
group consisting
of exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide,
semaglutide, and taspoglutide.
[0019] In one embodiment, the GLP-1 receptor agonist is selected from the
group consisting
of GLP-1(7-37) (SEQ ID NO: 1244); GLP-1(7-36)-N}2 (SEQ ID NO: 1245);
iiraglutide;
albiglutide; taspoglutid.e; dulaglutide, semaglutide, LY2428757; desamino-
His7,.. 2Arg 6,Lys34(Ne_7,,
Glu(N-a-hexadecanoyI)))-GLP-1(7-37) (core peptide disclosed as
SEQ ID NO: 1282); desamino-Illis7,Arg26,Lys34(Nc-octanoy1)-GLP-1(7-37) (SEQ ID
NO:
1283); Arg26,34,Lys38(M-(a)-carboxypentadecan.oy1))-GLP-1(7-38) (SEQ ID NO:
1284);
Arg26,34,Lys36(Ne./y_
Giu(N-a-hexadecanoy1)))-GLP-1(7-36) (core peptide disclosed as SEQ
ID NO: 1285); Aib8,35,Arg26,34,Phe31-GLP-1(7-36)) (SEQ ID NO: 1246);
FIXaa8EGTFTSDV5SYLEXaa22Xaa23AAKEFIXaa3oWLXaa33Xaa34G Xaa36Xaa37; wherein
Xaa3 is A, V, or Gr; Xaa.22 is G, K, or E; Xaa.23 is Q or K; Xaa:30 is A or E;
Xaa33 is V or K;
Xaa34 is K, N, or R; Xaa36 is R or G; and Xaa37 is G. H, P, or absent (SEQ ID
NO: 1247);
Arg34-GLP-I(7.37) (SEQ ID NO: 1248); G1u30-GLP-1(7-37) (SEQ ID NO: 1249);
Lys22-
GLP-1(7-37) (SEQ ID NO: 1250); Gly8.36,G1u22-GLP-1(7-37) (SEQ ID NO: 1.251);
u22,
y GLP-1(7-37) (SEQ ID NO: 1252); Gly8s36,G1u22,Lys33,.Asn34-GLP-1(7-
37)
(SEQ ID NO: 1253); Va18,G1u22,Lys33,Asn34,G1y36-GLP-1(7-37) (SEQ ID NO: 1254);
Gly8,36,G1u22,Pro37-GLP-1(7-37) (SEQ ID NO: 1255); 'Va18,G1u22,G1y36Pro37-GLP-
1(7-37)
(SEQ ID NO: 1256); Gly8,36,G1u22,Lys33, Asn34,Pro37-GLP-I(7-37) (SEQ ID NO:
1257);
va18,Giu22,Lys33,Asn34,Gly36,Pro37-GLP-1(7-37) (SEQ ID NO: 1258); Gly 8,36,
Giu22_GLp_1(7_
36) (SEQ ID NO: 1259); Va18,Glu22,G1y36-GILP-1(7-36) (SEQ ID NO: 1260);
Va18,G1u22,.Asn34,Gly36-GLP-1(7-36) (SEQ ID NO: 1261); and Gly8,36,G1u22,Asn34-
GLP-1(7-
36) (SEQ ID NO: 1262).
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[0020] In another embodiment, the subject is a mammal. In another embodiment,
the subject
is human. In another embodiment, the GIPR is human GIPR. In another
embodiment, the
administering is by parenteral injection. In another embodiment, the
administering is by
subcutaneous injection.
[0021] In another aspect the present disclosure provides an antigen binding
protein that
specifically binds to a human GIPR polypeptide and inhibits activation of GIPR
by GIP
ligand. In one embodiment, the antigen binding protein inhibits GIP ligand
binding to GIPR.
In another embodiment, the antigen binding protein is a human antigen binding
protein. In
another embodiment, the antigen binding protein is a human antibody. In
another
embodiment, the antigen binding protein is a monoclonal antibody.
[0022] In another aspect, the present disclosure provides a pharmaceutical
composition
comprising at least one antigen binding protein according to any one of the
foregoing
embodiments.
[0023] In another aspect, the present disclosure provides a nucleic acid
molecule encoding an
antigen binding protein according to any one of the foregoing embodiments.
[0024] In another aspect, the present disclosure provides a vector comprising
a nucleic acid
molecule encoding an antigen binding protein according to any one of the
foregoing
embodiments.
[0025] In another aspect, the present disclosure provides a host cell
comprising a nucleic acid
molecule encoding an antigen binding protein according to any one of the
foregoing
embodiments or a vector comprising a nucleic acid molecule encoding an antigen
binding
protein according to any one of the foregoing embodiments. In another aspect
the present
disclosure provides an antigen binding protein that specifically binds to a
human GIPR
polypeptide expressed by the vector.
[0026] In another aspect, the present disclosure provides a method of making
an antigen
binding protein according to any one of the foregoing embodiments, the method
comprising
expressing the antigen binding protein in a host cell that secretes the
antigen binding protein,
and then purifying the antigen binding protein from the cell culture media. In
another aspect
the present disclosure provides an antigen binding protein that specifically
binds to a human
GIPR polypeptide purified from the host cell.
[0027] In another aspect, the present disclosure provides an antigen binding
protein of any
one of the foregoing embodiments or a pharmaceutical composition of any one of
the
foregoing embodiments for use in therapy.
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DETAILED DESCRIPTION OF THE INVENTION
[0028] The present disclosure provides a method of treating a metabolic
disorder, such as a
disorder of glucose metabolism (e.g. Type 2 diabetes, elevated glucose levels,
elevated
insulin levels, dyslipidemia, metabolic syndrome (Syndrome X or insulin
resistance
syndrome), glucosuria, metabolic acidosis, Type 1 diabetes, obesity and
conditions
exacerbated by obesity) by blocking or interfering with the biological
activity of GIP. In one
embodiment, a therapeutically effective amount of an isolated human GIPR
binding protein is
administered to a subject in need thereof Methods of administration and
delivery are also
provided.
[0029] Recombinant polypeptide and nucleic acid methods used herein, including
in the
Examples, are generally those set forth in Sambrook et al., Molecular Cloning:
A Laboratory
Manual (Cold Spring Harbor Laboratory Press, 1989) or Current Protocols in
Molecular
Biology (Ausubel et al., eds., Green Publishers Inc. and Wiley and Sons 1994),
both of which
are incorporated herein by reference for any purpose.
[0030] The section headings used herein are for organizational purposes only
and are not to
be construed as limiting the subject matter described.
[0031] Unless otherwise defined herein, scientific and technical terms used in
connection
with the present application shall have the meanings that are commonly
understood by those
of ordinary skill in the art. Further, unless otherwise required by context,
singular terms shall
include pluralities and plural terms shall include the singular.
[0032] Generally, nomenclatures used in connection with, and techniques of,
cell and tissue
culture, molecular biology, immunology, microbiology, genetics and protein and
nucleic acid
chemistry and hybridization described herein are those well-known and commonly
used in
the art. The methods and techniques of the present application are generally
performed
according to conventional methods well known in the art and as described in
various general
and more specific references that are cited and discussed throughout the
present specification
unless otherwise indicated. See, e.g., Sambrook et al., Molecular Cloning: A
Laboratory
Manual, 3rd ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.
(2001),
Ausubel et al., Current Protocols in Molecular Biology, Greene Publishing
Associates (1992),
and Harlow and Lane Antibodies: A Laboratory Manual Cold Spring Harbor
Laboratory
Press, Cold Spring Harbor, N.Y. (1990), which are incorporated herein by
reference.
Enzymatic reactions and purification techniques are performed according to
manufacturer's
specifications, as commonly accomplished in the art or as described herein.
The terminology
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used in connection with, and the laboratory procedures and techniques of,
analytical
chemistry, synthetic organic chemistry, and medicinal and pharmaceutical
chemistry
described herein are those well-known and commonly used in the art. Standard
techniques
can be used for chemical syntheses, chemical analyses, pharmaceutical
preparation,
formulation, and delivery, and treatment of patients.
[0033] It should be understood that this invention is not limited to the
particular
methodology, protocols, and reagents, etc., described herein and as such may
vary. The
terminology used herein is for the purpose of describing particular
embodiments only, and is
not intended to limit the scope of the disclosed, which is defined solely by
the claims.
[0034] Other than in the operating examples, or where otherwise indicated, all
numbers
expressing quantities of ingredients or reaction conditions used herein should
be understood
as modified in all instances by the term "about." The term "about" when used
in connection
with percentages may mean 1%.
[0035] Following convention, as used herein "a" and "an" mean "one or more"
unless
specifically indicated otherwise.
[0036] As used herein, the terms "amino acid" and "residue" are
interchangeable and, when
used in the context of a peptide or polypeptide, refer to both naturally
occurring and synthetic
amino acids, as well as amino acid analogs, amino acid mimetics and non-
naturally occurring
amino acids that are chemically similar to the naturally occurring amino
acids.
[0037] A "naturally occurring amino acid" is an amino acid that is encoded by
the genetic
code, as well as those amino acids that are encoded by the genetic code that
are modified
after synthesis, e.g., hydroxyproline, y-carboxyglutamate, and 0-
phosphoserine. An amino
acid analog is a compound that has the same basic chemical structure as a
naturally occurring
amino acid, i.e., an a carbon that is bound to a hydrogen, a carboxyl group,
an amino group,
and an R group, e.g., homoserine, norleucine, methionine sulfoxide, methionine
methyl
sulfonium. Such analogs can have modified R groups (e.g., norleucine) or
modified peptide
backbones, but will retain the same basic chemical structure as a naturally
occurring amino
acid.
[0038] An "amino acid mimetic" is a chemical compound that has a structure
that is different
from the general chemical structure of an amino acid, but that functions in a
manner similar
to a naturally occurring amino acid. Examples include a methacryloyl or
acryloyl derivative
of an amide, (3-, y-, 6-amino acids (such as piperidine-4-carboxylic acid) and
the like.
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[0039] A "non-naturally occurring amino acid" is a compound that has the same
basic
chemical structure as a naturally occurring amino acid, but is not
incorporated into a growing
polypeptide chain by the translation complex. "Non-naturally occurring amino
acid" also
includes, but is not limited to, amino acids that occur by modification (e.g.,
posttranslational
modifications) of a naturally encoded amino acid (including but not limited
to, the 20
common amino acids) but are not themselves naturally incorporated into a
growing
polypeptide chain by the translation complex. A non-limiting lists of examples
of non-
naturally occurring amino acids that can be inserted into a polypeptide
sequence or
substituted for a wild-type residue in polypeptide sequence include 13-amino
acids,
homoamino acids, cyclic amino acids and amino acids with derivatized side
chains. Examples
include (in the L-form or D-form; abbreviated as in parentheses): citrulline
(Cit),
homocitrulline (hCit), Na-methylcitrulline (NMeCit), Na-methylhomocitrulline
(Na-
MeHoCit), ornithine (Orn), Na-Methylornithine (Na-MeOrn or NMeOrn), sarcosine
(Sar),
homolysine (hLys or hK), homoarginine (hArg or hR), homoglutamine (hQ),
Na-methylarginine (NMeR), Na-methylleucine (Na-MeL or NMeL), N-
methylhomolysine
(NMeHoK), Na-methylglutamine (NMeQ), norleucine (Nle), norvaline (Nva),
1,2,3,4-
tetrahydroisoquinoline (Tic), Octahydroindole-2-carboxylic acid (Oic), 3-(1-
naphthyDalanine
(1-Nal), 3-(2-naphthyDalanine (2-Nal), 1,2,3,4-tetrahydroisoquinoline (Tic), 2-
indanylglycine
(IgI), para-iodophenylalanine (pI-Phe), para-aminophenylalanine (4AmP or 4-
Amino-Phe), 4-
guanidino phenylalanine (Guf), glycyllysine (abbreviated "K(NE-glycyl)" or
"K(glycyl)" or
"K(gly)"), nitrophenylalanine (nitrophe), aminophenylalanine (aminophe or
Amino-Phe),
benzylphenylalanine (benzylphe), y-carboxyglutamic acid (y-carboxyglu),
hydroxyproline
(hydroxypro), p-carboxyl-phenylalanine (Cpa), a-aminoadipic acid (Aad), Na-
methyl valine
(NMeVal), N-a-methyl leucine (NMeLeu), Na-methylnorleucine (NMeNle),
cyclopentylglycine (Cpg), cyclohexylglycine (Chg), acetylarginine (acetylarg),
a, 13-
diaminopropionoic acid (Dpr), a, y-diaminobutyric acid (Dab), diaminopropionic
acid (Dap),
cyclohexylalanine (Cha), 4-methyl-phenylalanine (MePhe), 13, 13-diphenyl-
alanine (BiPhA),
aminobutyric acid (Abu), 4-phenyl-phenylalanine (or biphenylalanine; 4Bip), a-
amino-
isobutyric acid (Aib), beta-alanine, beta-aminopropionic acid, piperidinic
acid, aminocaprioic
acid, aminoheptanoic acid, aminopimelic acid, desmosine, diaminopimelic acid,
N-
ethylglycine, N-ethylaspargine, hydroxylysine, allo-hydroxylysine,
isodesmosine, allo-
isoleucine, N-methylglycine, N-methylisoleucine, N-methylvaline, 4-
hydroxyproline (Hyp),
y-carboxyglutamate, e-N,N,N-trimethyllysine, e-N-acetyllysine, 0-
phosphoserine, N-
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acetylserine, N-formylmethionine, 3-methylhistidine, 5-hydroxylysine, w-
methylarginine, 4-
Amino-O-Phthalic Acid (4APA), and other similar amino acids, and derivatized
forms of any
of those specifically listed.
[0040] The term "isolated nucleic acid molecule" refers to a single or double-
stranded
polymer of deoxyribonucleotide or ribonucleotide bases read from the 5' to the
3' end (e.g., a
GIPR nucleic acid sequence provided herein), or an analog thereof, that has
been separated
from at least about 50 percent of polypeptides, peptides, lipids,
carbohydrates,
polynucleotides or other materials with which the nucleic acid is naturally
found when total
nucleic acid is isolated from the source cells. Preferably, an isolated
nucleic acid molecule is
substantially free from any other contaminating nucleic acid molecules or
other molecules
that are found in the natural environment of the nucleic acid that would
interfere with its use
in polypeptide production or its therapeutic, diagnostic, prophylactic or
research use.
[0041] The term "isolated polypeptide" refers to a polypeptide (e.g., a GIPR
polypeptide
sequence provided herein or an antigen binding protein of the present
invention) that has been
separated from at least about 50 percent of polypeptides, peptides, lipids,
carbohydrates,
polynucleotides, or other materials with which the polypeptide is naturally
found when
isolated from a source cell. Preferably, the isolated polypeptide is
substantially free from any
other contaminating polypeptides or other contaminants that are found in its
natural
environment that would interfere with its therapeutic, diagnostic,
prophylactic or research
use.
[0042] The term "encoding" refers to a polynucleotide sequence encoding one or
more amino
acids. The term does not require a start or stop codon.
[0043] The terms "identical" and percent "identity," in the context of two or
more nucleic
acids or polypeptide sequences, refer to two or more sequences or subsequences
that are the
same. "Percent identity" means the percent of identical residues between the
amino acids or
nucleotides in the compared molecules and is calculated based on the size of
the smallest of
the molecules being compared. For these calculations, gaps in alignments (if
any) can be
addressed by a particular mathematical model or computer program (i.e., an
"algorithm").
Methods that can be used to calculate the identity of the aligned nucleic
acids or polypeptides
include those described in Computational Molecular Biology, (Lesk, A. M.,
ed.), (1988) New
York: Oxford University Press; Biocomputing Informatics and Genome Projects,
(Smith, D.
W., ed.), 1993, New York: Academic Press; Computer Analysis of Sequence Data,
Part I,
(Griffin, A. M., and Griffin, H. G., eds.), 1994, New Jersey: Humana Press;
von Heinje, G.,
(1987) Sequence Analysis in Molecular Biology, New York: Academic Press;
Sequence
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Analysis Primer, (Gribskov, M. and Devereux, J., eds.), 1991, New York: M.
Stockton Press;
and Carillo etal., (1988) SIAM J. Applied Math. 48:1073.
[0044] In calculating percent identity, the sequences being compared are
aligned in a way
that gives the largest match between the sequences. The computer program used
to determine
percent identity is the GCG program package, which includes GAP (Devereux et
al., (1984)
Nucl. Acid Res. 12:387; Genetics Computer Group, University of Wisconsin,
Madison, WI).
The computer algorithm GAP is used to align the two polypeptides or
polynucleotides for
which the percent sequence identity is to be determined. The sequences are
aligned for
optimal matching of their respective amino acid or nucleotide (the "matched
span", as
determined by the algorithm). A gap opening penalty (which is calculated as 3x
the average
diagonal, wherein the "average diagonal" is the average of the diagonal of the
comparison
matrix being used; the "diagonal" is the score or number assigned to each
perfect amino acid
match by the particular comparison matrix) and a gap extension penalty (which
is usually
1/10 times the gap opening penalty), as well as a comparison matrix such as
PAM 250 or
BLOSUM 62 are used in conjunction with the algorithm. In certain embodiments,
a standard
comparison matrix (see, Dayhoff et al., (1978) Atlas of Protein Sequence and
Structure
5:345-352 for the PAM 250 comparison matrix; Henikoff et al., (1992) Proc.
Natl. Acad. Sci.
U.S.A. 89:10915-10919 for the BLOSUM 62 comparison matrix) is also used by the
algorithm.
[0045] Recommended parameters for determining percent identity for
polypeptides or
nucleotide sequences using the GAP program are the following:
[0046] Algorithm: Needleman et al., 1970, J. Mol. Biol. 48:443-453;
[0047] Comparison matrix: BLOSUM 62 from Henikoff et al., 1992, supra;
[0048] Gap Penalty: 12 (but with no penalty for end gaps)
[0049] Gap Length Penalty: 4
[0050] Threshold of Similarity: 0
[0051] Certain alignment schemes for aligning two amino acid sequences can
result in
matching of only a short region of the two sequences, and this small aligned
region can have
very high sequence identity even though there is no significant relationship
between the two
full-length sequences. Accordingly, the selected alignment method (e.g., the
GAP program)
can be adjusted if so desired to result in an alignment that spans at least 50
contiguous amino
acids of the target polypeptide.
[0052] The terms "GIPR polypeptide" and "GIPR protein" are used
interchangeably and
mean a naturally-occurring wild-type polypeptide expressed in a mammal, such
as a human
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or a mouse, and includes naturally occurring alleles (e.g., naturally
occurring allelic forms of
human GIPR protein). For purposes of this disclosure, the term "GIPR
polypeptide" can be
used interchangeably to refer to any full-length GIPR polypeptide, e.g., SEQ
ID NO: 1201,
which consists of 466 amino acid residues and which is encoded by the
nucleotide sequence
SEQ ID NO: 1202, or SEQ ID NO: 1203, which consists of 430 amino acid residues
and
which is encoded by the nucleic acid sequence SEQ ID NO: 1204, or SEQ ID NO:
1205,
which consists of 493 amino acid resides and which is encoded by the nucleic
acid sequence
of SEQ ID NO: 1206, or SEQ ID NO: 1207, which consists of 460 amino acids
residues and
which is encoded by the nucleic acid sequence of SEQ ID NO: 1208, or SEQ ID
NO: 1209,
which consists of 230 amino acids residues and which is encoded by the nucleic
acid
sequence of SEQ ID NO: 1210.
[0053] The term "GIPR polypeptide" also encompasses a GIPR polypeptide in
which a
naturally occurring GIPR polypeptide sequence (e.g., SEQ ID NOs: 1201, 1203 or
1205) has
been modified. Such modifications include, but are not limited to, one or more
amino acid
substitutions, including substitutions with non-naturally occurring amino
acids non-naturally-
occurring amino acid analogs and amino acid mimetics.
[0054] In various embodiments, a GIPR polypeptide comprises an amino acid
sequence that
is at least about 85 percent identical to a naturally-occurring GIPR
polypeptide (e.g., SEQ ID
NOs: 1201, 1203 or 1205). In other embodiments, a GIPR polypeptide comprises
an amino
acid sequence that is at least about 90 percent, or about 95, 96, 97, 98, or
99 percent identical
to a naturally-occurring GIPR polypeptide amino acid sequence (e.g., SEQ ID
NOs: 1201,
1203 or 1205). Such GIPR polypeptides preferably, but need not, possess at
least one activity
of a wild-type GIPR polypeptide, such as the ability to bind GIP. The present
invention also
encompasses nucleic acid molecules encoding such GIPR polypeptide sequences.
[0055] The terms "GIPR activity assay" (also referred to as a "GIPR functional
assay")
means an assay that can be used to measure GIP or a GIP binding protein
activity in a cellular
setting. In one embodiment, the "activity" (or "functional") assay" can be a
cAMP assay in
GIPR expressing cells, in which GIP can induce cAMP signal, and the activity
of a
GIP/GIPR binding protein could be measured in the presence/absence of GIP
ligand, in
which IC50/EC50 and degree of inhibition/activation can be obtained
(Biochemical and
Biophysical Research Communications (2002) 290:1420-1426). In another
embodiment, the
"activity" (or "functional") assay can be an insulin secretion assay in
pancreatic beta cells, in
which GIP can induce glucose-dependent insulin secretion, and the activity of
a GIP/GIPR
binding protein could be measured in the presence/absence of GIP ligand, in
which
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IC50/EC50 and degree of inhibition/activation can be obtained (Biochemical and
Biophysical
Research Communications (2002) 290:1420-1426).
[0056] The term "GIPR binding assay" means an assay that can be used to
measure binding
of GIP to GIPR. In one embodiment, "GIPR binding assay" can be an assay using
FMAT or
FACS that measures fluorescence-labeled GIP binding to GIPR expression cells,
and
GIP/GIPR binding protein's activity can be measured for displacing
fluorescence-labeled GIP
binding to GIPR expression cells. In another embodiment, "GIPR binding assay"
can be an
assay that measures radioactive-labeled GIP binding to GIPR expression cells,
and GIP/GIPR
binding protein's activity can be measured for displacing radioactive labeled
GIP binding to
GIPR expression cells (Biochimica et Biophysica Acta (2001) 1547:143-155).
[0057] The terms "GIP", "Gastric inhibitory polypeptide", "glucose-dependent
insulinotropic
peptide" and "GIP ligand" are used interchangeably and mean a naturally-
occurring wild-
type polypeptide expressed in a mammal, such as a human or a mouse, and
includes naturally
occurring alleles (e.g., naturally occurring allelic forms of human GIP
protein). For purposes
of this disclosure, the term "GIP" can be used interchangeably to refer to any
mature GIP
polypeptide.
[0058] The 42 amino acid sequence of mature human GIP is:
[0059] YAEGTFISDY SIAMDKIHQQ DFVNWLLAQK GKKNDWKHNI TQ (M)1131\14a
1211)
[0060] and is encoded by the DNA sequence:
[0061] tatgcggaag gcacctttat tagcgattat agcattgcga tggataaaat
tcatcagcag gattttgtga actggctgct ggcgcagaaa ggcaaaaaaa
acgattggaa acataacatt acccag (SEQ ID NO: 1212).
[0062] The 42 amino acid sequence of mature murine GIP is:
[0063] YAEGTFISDY SIAMDKIRQQ DFVNWLLAQR GKKSDWKHNI TQ (SEQ ID NO:
1213)
[0064] and is encoded by the DNA sequence:
[0065] tatgcggaag gcacctttat tagcgattat agcattgcga tggataaaat
tcgccagcag gattttgtga actggctgct ggcgcagcgc ggcaaaaaaa
gcgattggaa acataacatt acccag (SEQ ID NO: 1214).
[0066] The 42 amino acid sequence of mature rat GIP is:
100671 YAEGTFISDY SIAMDKIRQQ DFVNWLLAQK GKKNDWKHNL TQ(SWIDMI
1215)
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[0068] and is encoded by the DNA sequence:
[0069] tatgcggaag gcacctttat tagcgattat agcattgcga tggataaaat
tcgccagcag gattttgtga actggctgctg gcgcagaaag gcaaaaaaaa
cgattggaaa cataacctga cccag (SEQ IDNO: 1216).
[0070] An "antigen binding protein" as used herein means any protein that
specifically binds
a specified target antigen, such as a GIPR polypeptide (e.g., a human GIPR
polypeptide such
as provided in SEQ ID NOs: 1201, 1203 or 1205). The term encompasses intact
antibodies
that comprise at least two full-length heavy chains and two full-length light
chains, as well as
derivatives, variants, fragments, and mutations thereof Examples of antibody
fragments
include Fab, Fab', F(ab1)2, and Fv fragments. An antigen binding protein also
includes domain
antibodies such as nanobodies and scFvs as described further below.
[0071] In general, a GIPR antigen binding protein is said to "specifically
bind" its target
antigen GIPR when the antigen binding protein exhibits essentially background
binding to
non-GIPR molecules. An antigen binding protein that specifically binds GIPR
may, however,
cross-react with GIPR polypeptides from different species. Typically, a GIPR
antigen binding
protein specifically binds human GIPR when the dissociation constant (KD) is
<10-7M as
measured via a surface plasma resonance technique (e.g., BIACore, GE-
Healthcare Uppsala,
Sweden) or Kinetic Exclusion Assay (KinExA, Sapidyne, Boise, Idaho). A GIPR
antigen
binding protein specifically binds human GIPR with "high affinity" when the KD
is <5x 10-9
M, and with "very high affinity" when the KD is <5x 10-19 M, as measured using
methods
described.
[0072] "Antigen binding region" means a protein, or a portion of a protein,
that specifically
binds a specified antigen. For example, that portion of an antigen binding
protein that
contains the amino acid residues that interact with an antigen and confer on
the antigen
binding protein its specificity and affinity for the antigen is referred to as
"antigen binding
region." An antigen binding region typically includes one or more
"complementary binding
regions" ("CDRs") of an immunoglobulin, single-chain immunoglobulin, or
camelid
antibody. Certain antigen binding regions also include one or more "framework"
regions. A
"CDR" is an amino acid sequence that contributes to antigen binding
specificity and affinity.
"Framework" regions can aid in maintaining the proper conformation of the CDRs
to
promote binding between the antigen binding region and an antigen.
[0073] A "recombinant protein", including a recombinant GIPR antigen binding
protein, is a
protein made using recombinant techniques, i.e., through the expression of a
recombinant
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nucleic acid as described herein. Methods and techniques for the production of
recombinant
proteins are well known in the art.
[0074] The term "antibody" refers to an intact immunoglobulin of any isotype,
or a fragment
thereof that can compete with the intact antibody for specific binding to the
target antigen,
and includes, for instance, chimeric, humanized, fully human, and bispecific
antibodies. An
"antibody" as such is a species of an antigen binding protein. An intact
antibody generally
will comprise at least two full-length heavy chains and two full-length light
chains.
Antibodies may be derived solely from a single source, or may be "chimeric,"
that is,
different portions of the antibody may be derived from two different
antibodies as described
further below. The antigen binding proteins, antibodies, or binding fragments
may be
produced in hybridomas, by recombinant DNA techniques, or by enzymatic or
chemical
cleavage of intact antibodies.
[0075] The term "light chain" as used with respect to an antibody or fragments
thereof
includes a full-length light chain and fragments thereof having sufficient
variable region
sequence to confer binding specificity. A full-length light chain includes a
variable region
domain, VL, and a constant region domain, CL. The variable region domain of
the light chain
is at the amino-terminus of the polypeptide. Light chains include kappa chains
and lambda
chains.
[0076] The term "heavy chain" as used with respect to an antibody or fragment
thereof
includes a full-length heavy chain and fragments thereof having sufficient
variable region
sequence to confer binding specificity. A full-length heavy chain includes a
variable region
domain, VH, and three constant region domains, CH1, CH2, and CH3. The VH
domain is at
the amino-terminus of the polypeptide, and the CH domains are at the carboxyl-
terminus,
with the CH3 being closest to the carboxy-terminus of the polypeptide. Heavy
chains may be
of any isotype, including IgG (including IgGl, IgG2, IgG3 and IgG4 subtypes),
IgA
(including IgAl and IgA2 subtypes), IgM and IgE.
[0077] The term "immunologically functional fragment" (or simply "fragment")
of an
antibody or immunoglobulin chain (heavy or light chain), as used herein, is an
antigen
binding protein comprising a portion (regardless of how that portion is
obtained or
synthesized) of an antibody that lacks at least some of the amino acids
present in a full-length
chain but which is capable of specifically binding to an antigen. Such
fragments are
biologically active in that they bind specifically to the target antigen and
can compete with
other antigen binding proteins, including intact antibodies, for specific
binding to a given
epitope.
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[0078] These biologically active fragments may be produced by recombinant DNA
techniques, or may be produced by enzymatic or chemical cleavage of antigen
binding
proteins, including intact antibodies. Immunologically functional
immunoglobulin fragments
include, but are not limited to, Fab, Fab', and F(ab1)2 fragments.
[0079] In another embodiment, Fvs, domain antibodies and seFvs, and may be
derived from
an antibody of the present invention.
[0080] It is contemplated further that a functional portion of the antigen
binding proteins
disclosed herein, for example, one or more CDRs, could be covalently bound to
a second
protein or to a small molecule to create a therapeutic agent directed to a
particular target in
the body, possessing bifunctional therapeutic properties, or having a
prolonged serum half-
life.
[0081] A "Fab fragment" is comprised of one light chain and the CH1 and
variable regions of
one heavy chain. The heavy chain of a Fab molecule cannot form a disulfide
bond with
another heavy chain molecule.
[0082] An "Fe" region contains two heavy chain fragments comprising the CH2
and CH3
domains of an antibody. The two heavy chain fragments are held together by two
or more
disulfide bonds and by hydrophobic interactions of the CH3 domains.
[0083] In certain embodiments, one or more amino acid modifications may be
introduced
into the Fc region of an antibody provided herein, thereby generating an Fc
region variant.
The Fc region variant may comprise a human Fc region sequence (e.g., a human
IgGl, IgG2,
IgG3 or IgG4 Fc region) comprising an amino acid modification (e.g. a
substitution) at one or
more amino acid positions.
[0084] In certain embodiments, the invention contemplates an antibody variant
that possesses
some but not all effector functions, which make it a desirable candidate for
applications in
which the half life of the antibody in vivo is important yet certain effector
functions (such as
complement and ADCC) are unnecessary or deleterious. In vitro and/or in vivo
cytotoxicity
assays can be conducted to confirm the reduction/depletion of CDC and/or ADCC
activities.
For example, Fc receptor (FcR) binding assays can be conducted to ensure that
the antibody
lacks Fc.gamma.R binding (hence likely lacking ADCC activity), but retains
FcRn binding
ability. The primary cells for mediating ADCC, NK cells, express Fe(RIII only,
whereas
monocytes express Fe(RI, Fe(RII and Fe(RIII. FcR expression on hematopoietic
cells is
summarized in Table 3 on page 464 of Ravetch and Kinet, Annu. Rev. Immunol.
9:457-492
(1991). Non-limiting examples of in vitro assays to assess ADCC activity of a
molecule of
interest is described in U.S. Pat. No. 5,500,362 (see, e.g. Hellstrom, I. et
al. Proc. Nat'l Acad.
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Sci. USA 83:7059-7063 (1986)) and Hellstrom, I et al., Proc. Nat'l Acad. Sci.
USA 82:1499-
1502 (1985); 5,821,337 (see Bruggemann, M. etal., J. Exp. Med. 166:1351-1361
(1987)).
Alternatively, non-radioactive assays methods may be employed (see, for
example,
ACTI.TM. non-radioactive cytotoxicity assay for flow cytometry
(CellTechnology, Inc.
Mountain View, Calif.; and CytoTox 96® non-radioactive cytotoxicity assay
(Promega,
Madison, Wis.). Useful effector cells for such assays include peripheral blood
mononuclear
cells (PBMC) and Natural Killer (NK) cells. Alternatively, or additionally,
ADCC activity of
the molecule of interest may be assessed in vivo, e.g., in a animal model such
as that
disclosed in Clynes et al. Proc. Nat'l Acad. Sci. USA 95:652-656 (1998). Clq
binding assays
may also be carried out to confirm that the antibody is unable to bind Clq and
hence lacks
CDC activity. See, e.g., Clq and C3c binding ELISA in WO 2006/029879 and WO
2005/100402. To assess complement activation, a CDC assay may be performed
(see, for
example, Gazzano-Santoro et al., J. Immunol. Methods 202:163 (1996); Cragg, M.
S. etal.,
Blood 101:1045-1052 (2003); and Cragg, M. S. and M. J. Glennie, Blood 103:2738-
2743
(2004)). FcRn binding and in vivo clearance/half life determinations can also
be performed
using methods known in the art (see, e.g., Petkova, S. B. etal., Int'l.
Immunol. 18(12):1759-
1769 (2006)).
[0085] In some embodiments, one or more amino acid modifications may be
introduced into
the Fc portion of the antibody provided herein in order to increase IgG
binding to the
neonatal Fc receptor. In certain embodiments, the antibody comprises the
following three
mutations according to EU numbering: M252Y, 5254T, and T256E (the "YTE
mutation")
(U.S. Pat. No. 8,697,650; see also Dall'Acqua et al., Journal of Biological
Chemistry
281(33):23514-23524 (2006). In certain embodiments, the YTE mutation does not
affect the
ability of the antibody to bind to its cognate antigen. In certain
embodiments, the YTE
mutation increases the antibody's serum half-life compared to the native
(i.e., non-YTE
mutant) antibody. In some embodiments, the YTE mutation increases the serum
half-life of
the antibody by 3-fold compared to the native (i.e., non-YTE mutant) antibody.
In some
embodiments, the YTE mutation increases the serum half-life of the antibody by
2-fold
compared to the native (i.e., non-YTE mutant) antibody. In some embodiments,
the YTE
mutation increases the serum half-life of the antibody by 4-fold compared to
the native (i.e.,
non-YTE mutant) antibody. In some embodiments, the YTE mutation increases the
serum
half-life of the antibody by at least 5-fold compared to the native (i.e., non-
YTE mutant)
antibody. In some embodiments, the YTE mutation increases the serum half-life
of the
antibody by at least 10-fold compared to the native (i.e., non-YTE mutant)
antibody. See,
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e.g., U.S. Pat. No. 8,697,650; see also Dall'Acqua et al., Journal of
Biological Chemistry
281(33):23514-23524 (2006).
[0086] In certain embodiments, the YTE mutant provides a means to modulate
antibody-
dependent cell-mediated cytotoxicity (ADCC) activity of the antibody. In
certain
embodiments, the YTEO mutant provides a means to modulate ADCC activity of a
humanized IgG antibody directed against a human antigen. See, e.g., U.S. Pat.
No. 8,697,650;
see also Dall'Acqua et al., Journal of Biological Chemistry 281(33):23514-
23524 (2006).
In certain embodiments, the YTE mutant allows the simultaneous modulation of
serum half-
life, tissue distribution, and antibody activity (e.g., the ADCC activity of
an IgG antibody).
See, e.g., U.S. Pat. No. 8,697,650; see also Dall'Acqua et al., Journal of
Biological Chemistry
281(33):23514-23524 (2006).
[0087] Antibodies with reduced effector function include those with
substitution of one or
more of Fc region residues 238, 265, 269, 270, 297, 327 and 329 according to
EU numbering
(U.S. Pat. No. 6,737,056). Such Fc mutants include Fc mutants with
substitutions at two or
more of amino acid positions 265, 269, 270, 297 and 327 according to EU
numbering,
including the so-called "DANA" Fc mutant with substitution of residues 265 and
297 to
alanine according to EU numbering (i.e., D265A and N297A according to EU
numbering)
(U.S. Pat. No. 7,332,581). In certain embodiments the Fc mutant comprises the
following two
amino acid substitutions: D265A and N297A. In certain embodiments the Fc
mutant consists
of the following two amino acid substitutions: D265A and N297A.
[0088] In certain embodiments, the proline at p05iti0n329 (EU numbering)
(P329) of a wild-
type human Fc region is substituted with glycine or arginine or an amino acid
residue large
enough to destroy the proline sandwich within the Fc/Fc.gamma. receptor
interface, that is
formed between the P329 of the Fc and tryptophane residues W87 and W110 of
FcgRIII
(Sondermann et al.: Nature 406, 267-273 (20 Jul. 2000)). In a further
embodiment, at least
one further amino acid substitution in the Fc variant is 5228P, E233P, L234A,
L235A,
L235E, N297A, N297D, or P331S and still in another embodiment said at least
one further
amino acid substitution is L234A and L235A of the human IgG1 Fc region or
5228P and
L235E of the human IgG4 Fc region, all according to EU numbering (U.S. Pat.
No. 8,969,526
which is incorporated by reference in its entirety).
[0089] In certain embodiments, a polypeptide comprises the Fc variant of a
wild-type human
IgG Fc region wherein the polypeptide has P329 of the human IgG Fc region
substituted with
glycine and wherein the Fc variant comprises at least two further amino acid
substitutions at
L234A and L235A of the human IgG1 Fc region or 5228P and L235E of the human
IgG4 Fc
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region, and wherein the residues are numbered according to the EU numbering
(U.S. Pat. No.
8,969,526 which is incorporated by reference in its entirety). In certain
embodiments, the
polypeptide comprising the P329G, L234A and L235A (EU numbering) substitutions
exhibit
a reduced affinity to the human Fc.gamma.RIIIA and Fc.gamma.RIIA, for down-
modulation
of ADCC to at least 20% of the ADCC induced by the polypeptide comprising the
wildtype
human IgG Fc region, and/or for down-modulation of ADCP (U.S. Pat. No.
8,969,526 which
is incorporated by reference in its entirety).
[0090] In a specific embodiment the polypeptide comprising an Fc variant of a
wildtype
human Fc polypeptide comprises a triple mutation: an amino acid substitution
at position
Pro329, a L234A and a L235A mutation according to EU numbering (P329/LALA)
(U.S.
Pat. No. 8,969,526 which is incorporated by reference in its entirety). In
specific
embodiments, the polypeptide comprises the following amino acid substitutions:
P329G,
L234A, and L235A according to EU numbering.
[0091] Certain antibody variants with improved or diminished binding to FcRs
are described.
(See, e.g., U.S. Pat. No. 6,737,056; WO 2004/056312, and Shields et al., J.
Biol. Chem. 9(2):
6591-6604 (2001).)
[0092] In certain embodiments, an antibody variant comprises an Fc region with
one or more
amino acid substitutions which improve ADCC, e.g., substitutions at positions
298, 333,
and/or 334 of the Fc region (EU numbering).
[0093] In some embodiments, alterations are made in the Fc region that result
in altered (i. e.,
either improved or diminished) Clq binding and/or Complement Dependent
Cytotoxicity
(CDC), e.g., as described in U.S. Pat. No. 6,194,551, WO 99/51642, and
Idusogie et al. J
Immunol. 164: 4178-4184 (2000).
[0094] Antibodies with increased half lives and improved binding to the
neonatal Fc receptor
(FcRn), which is responsible for the transfer of maternal IgGs to the fetus
(Guyer et al., J.
Immunol. 117:587 (1976) and Kim et al., J. Immunol. 24:249 (1994)), are
described in
U52005/0014934A1 (Hinton et al.).
[0095] Those antibodies comprise an Fc region with one or more substitutions
therein which
improve binding of the Fc region to FcRn. Such Fc variants include those with
substitutions
at one or more of Fc region residues: 238, 256, 265, 272, 286, 303, 305, 307,
311, 312, 317,
340, 356, 360, 362, 376, 378, 380, 382, 413, 424 or 434, e.g., substitution of
Fc region
residue 434 (U.S. Pat. No. 7,371,826) according to EU numbering. See also
Duncan &
Winter, Nature 322:738-40 (1988); U.S. Pat. No. 5,648,260; U.S. Pat. No.
5,624,821; and
WO 94/29351 concerning other examples of Fc region variants.
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[0096] An "Fab' fragment" contains one light chain and a portion of one heavy
chain that
contains the VH domain and the CH1 domain and also the region between the CH1
and CH2
domains, such that an interchain disulfide bond can be formed between the two
heavy chains
of two Fab' fragments to form an F(ab')2 molecule.
[0097] An "F(ab')2 fragment" contains two light chains and two heavy chains
containing a
portion of the constant region between the CH1 and CH2 domains, such that an
interchain
disulfide bond is formed between the two heavy chains. A F(ab')2 fragment thus
is composed
of two Fab' fragments that are held together by a disulfide bond between the
two
heavy chains.
[0098] The "Fv region" comprises the variable regions from both the heavy and
light chains,
but lacks the constant regions.
[0099] "Single chain antibodies" or "scFvs" are Fv molecules in which the
heavy and light
chain variable regions have been connected by a flexible linker to form a
single polypeptide
chain, which forms an antigen-binding region. scFvs are discussed in detail in
International
Patent Application Publication No. WO 88/01649 and United States Patent Nos.
4,946,778
and No. 5,260,203, the disclosures of which are incorporated by reference.
101001 A "domain antibody" or "single chain immunoglobulin" is an
immunologically
functional immunoglobulin fragment containing only the variable region of a
heavy chain or
the variable region of a light chain. Examples of domain antibodies include
Nanobodies0. In
some instances, two or more VH regions are covalently joined with a peptide
linker to create
a bivalent domain antibody. The two VH regions of a bivalent domain antibody
may target
the same or different antigens.
101011 A "bivalent antigen binding protein" or "bivalent antibody" comprises
two antigen
binding regions. In some instances, the two binding regions have the same
antigen
specificities. Bivalent antigen binding proteins and bivalent antibodies may
be bispecific, see,
infra.
[0102] A multispecific antigen binding protein" or "multispecific antibody" is
one that
targets more than one antigen or epitope.
[0103] A "bispecific," "dual-specific" or "bifunctional" antigen binding
protein or antibody
is a hybrid antigen binding protein or antibody, respectively, having two
different antigen
binding sites. Bispecific antigen binding proteins and antibodies are a
species of multispecific
antigen binding protein or multispecific antibody and may be produced by a
variety of
methods including, but not limited to, fusion of hybridomas or linking of Fab'
fragments. See,
e.g., Songsivilai and Lachmann, 1990, Clin. Exp. Immunol. 79:315-321; Kostelny
et al.,
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1992, J. Immunol. 148:1547-1553. The two binding sites of a bispecific antigen
binding
protein or antibody will bind to two different epitopes, which may reside on
the same or
different protein targets.
[0104] The term "compete" when used in the context of antigen binding proteins
(e.g.,
antibodies) means competition between antigen binding proteins is determined
by an assay in
which the antigen binding protein (e.g., antibody or immunologically
functional fragment
thereof) under test prevents or inhibits specific binding of a reference
antigen binding protein
to a common antigen (e.g., GIPR or a fragment thereof). Numerous types of
competitive
binding assays can be used, for example: solid phase direct or indirect
radioimmunoassay
(RIA), solid phase direct or indirect enzyme immunoassay (ETA), sandwich
competition
assay (see, e.g., Stahli et al., 1983, Methods in Enzymology 9:242-253); solid
phase direct
biotin-avidin ETA (see, e.g., Kirkland et al., 1986, J. Immunol. 137:3614-
3619) solid phase
direct labeled assay, solid phase direct labeled sandwich assay (see, e.g.,
Harlow and Lane,
1988, Antibodies, A Laboratory Manual, Cold Spring Harbor Press); solid phase
direct label
RIA using 1-125 label (see, e.g., Morel et al., 1988, Molec. Immunol. 25:7-
15); solid phase
direct biotin-avidin ETA (see, e.g., Cheung, et al., 1990, Virology 176:546-
552); and direct
labeled RIA (Moldenhauer et al., 1990, Scand. J. Immunol. 32:77-82).
Typically, such an
assay involves the use of purified antigen bound to a solid surface or cells
bearing either of
these, an unlabeled test antigen binding protein and a labeled reference
antigen binding
protein. Competitive inhibition is measured by determining the amount of label
bound to the
solid surface or cells in the presence of the test antigen binding protein.
Usually the test
antigen binding protein is present in excess. Additional details regarding
methods for
determining competitive binding are provided in the examples herein. Usually,
when a
competing antigen binding protein is present in excess, it will inhibit
specific binding of a
reference antigen binding protein to a common antigen by at least 40%, 45%,
50%, 55%,
60%, 65%, 70% or 75%. In some instances, binding is inhibited by at least 80%,
85%, 90%,
95%, or 97% or more.
[0105] The term "antigen" refers to a molecule or a portion of a molecule
capable of being
bound by a selective binding agent, such as an antigen binding protein
(including, e.g., an
antibody), and additionally capable of being used in an animal to produce
antibodies capable
of binding to that antigen. An antigen may possess one or more epitopes that
are capable of
interacting with different antigen binding proteins, e.g., antibodies.
[0106] The term "epitope" is the portion of a molecule that is bound by an
antigen binding
protein (for example, an antibody). The term includes any determinant capable
of specifically
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binding to an antigen binding protein, such as an antibody. An epitope can be
contiguous or
non-contiguous (discontinuous) (e.g., in a polypeptide, amino acid residues
that are not
contiguous to one another in the polypeptide sequence but that within in
context of the
molecule are bound by the antigen binding protein). A conformational epitope
is an epitope
that exists within the conformation of an active protein but is not present in
a denatured
protein. In certain embodiments, epitopes may be mimetic in that they comprise
a three
dimensional structure that is similar to an epitope used to generate the
antigen binding
protein, yet comprise none or only some of the amino acid residues found in
that epitope used
to generate the antigen binding protein. Most often, epitopes reside on
proteins, but in some
instances may reside on other kinds of molecules, such as nucleic acids.
Epitope determinants
may include chemically active surface groupings of molecules such as amino
acids, sugar
side chains, phosphoryl or sulfonyl groups, and may have specific three
dimensional
structural characteristics, and/or specific charge characteristics. Generally,
antigen binding
proteins specific for a particular target antigen will preferentially
recognize an epitope on the
target antigen in a complex mixture of proteins and/or macromolecules.
[0107] As used herein, "substantially pure" means that the described species
of molecule is
the predominant species present, that is, on a molar basis it is more abundant
than any other
individual species in the same mixture. In certain embodiments, a
substantially pure molecule
is a composition wherein the object species comprises at least 50% (on a molar
basis) of all
macromolecular species present. In other embodiments, a substantially pure
composition will
comprise at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% of all
macromolecular
species present in the composition. In other embodiments, the object species
is purified to
essential homogeneity wherein contaminating species cannot be detected in the
composition
by conventional detection methods and thus the composition consists of a
single detectable
macromolecular species.
[0108] The term "treating" refers to any indicia of success in the treatment
or amelioration of
an injury, pathology or condition, including any objective or subjective
parameter such as
abatement; remission; diminishing of symptoms or making the injury, pathology
or condition
more tolerable to the patient; slowing in the rate of degeneration or decline;
making the final
point of degeneration less debilitating; improving a patient's physical or
mental well-being.
The treatment or amelioration of symptoms can be based on objective or
subjective
parameters; including the results of a physical examination, neuropsychiatric
exams, and/or a
psychiatric evaluation. For example, certain methods presented herein
successfully treat
cardiovascular disease such as atherosclerosis by decreasing the incidence of
cardiovascular
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disease, causing remission of cardiovascular disease and/or ameliorating a
symptom
associated with cardiovascular disease.
[0109] An "effective amount" is generally an amount sufficient to reduce the
severity and/or
frequency of symptoms, eliminate the symptoms and/or underlying cause, prevent
the
occurrence of symptoms and/or their underlying cause, and/or improve or
remediate the
damage that results from or is associated with the disease state (e.g.,
diabetes, obesity,
dyslipidemia, elevated glucose levels, elevated insulin levels or diabetic
nephropathy. In
some embodiments, the effective amount is a therapeutically effective amount
or a
prophylactically effective amount. A "therapeutically effective amount" is an
amount
sufficient to remedy a disease state (e.g. atherosclerosis) or symptoms,
particularly a state or
symptoms associated with the disease state, or otherwise prevent, hinder,
retard or reverse the
progression of the disease state or any other undesirable symptom associated
with the disease
in any way whatsoever. A "prophylactically effective amount" is an amount of a
pharmaceutical composition that, when administered to a subject, will have the
intended
prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence)
of the disease
state, or reducing the likelihood of the onset (or reoccurrence) of the
disease state or
associated symptoms. The full therapeutic or prophylactic effect does not
necessarily occur
by administration of one dose, and may occur only after administration of a
series of doses.
Thus, a therapeutically or prophylactically effective amount may be
administered in one or
more administrations.
[0110] The terms "therapeutically effective dose" and "therapeutically
effective amount," as
used herein, means an amount of a GIPR binding protein that elicits a
biological or medicinal
response in a tissue system, animal, or human being sought by a researcher,
physician, or
other clinician, which includes alleviation or amelioration of the symptoms of
the disease or
disorder being treated, i.e., an amount of a GIPR binding protein that
supports an observable
level of one or more desired biological or medicinal response, for example
lowering blood
glucose, insulin, triglyceride, or cholesterol levels; reducing body weight;
or improving
glucose tolerance, energy expenditure, or insulin sensitivity.
[0111] The term "polynucleotide" or "nucleic acid" includes both single-
stranded and
double-stranded nucleotide polymers. The nucleotides comprising the
polynucleotide can be
ribonucleotides or deoxyribonucleotides or a modified form of either type of
nucleotide. The
modifications include base modifications such as bromouridine and inosine
derivatives,
ribose modifications such as 2',3'-dideoxyribose, and intemucleotide linkage
modifications
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such as phosphorothioate, phosphorodithioate, phosphoroselenoate,
phosphorodiselenoate,
phosphoroanilothioate, phoshoraniladate and phosphoroamidate.
[0112] The term "oligonucleotide" means a polynucleotide comprising 200 or
fewer
nucleotides. In some embodiments, oligonucleotides are 10 to 60 bases in
length. In other
embodiments, oligonucleotides are 12, 13, 14, 15, 16, 17, 18, 19, or 20 to 40
nucleotides in
length. Oligonucleotides may be single stranded or double stranded, e.g., for
use in the
construction of a mutant gene. Oligonucleotides may be sense or antisense
oligonucleotides.
An oligonucleotide can include a label, including a radiolabel, a fluorescent
label, a hapten or
an antigenic label, for detection assays. Oligonucleotides may be used, for
example, as PCR
primers, cloning primers or hybridization probes.
[0113] An "isolated nucleic acid molecule" means a DNA or RNA of genomic,
mRNA,
cDNA, or synthetic origin or some combination thereof which is not associated
with all or a
portion of a polynucleotide in which the isolated polynucleotide is found in
nature, or is
linked to a polynucleotide to which it is not linked in nature. For purposes
of this disclosure,
it should be understood that "a nucleic acid molecule comprising" a particular
nucleotide
sequence does not encompass intact chromosomes. Isolated nucleic acid
molecules
"comprising" specified nucleic acid sequences may include, in addition to the
specified
sequences, coding sequences for up to ten or even up to twenty other proteins
or portions
thereof, or may include operably linked regulatory sequences that control
expression of the
coding region of the recited nucleic acid sequences, and/or may include vector
sequences.
[0114] Unless specified otherwise, the left-hand end of any single-stranded
polynucleotide
sequence discussed herein is the 5' end; the left-hand direction of double-
stranded
polynucleotide sequences is referred to as the 5' direction. The direction of
5' to 3' addition of
nascent RNA transcripts is referred to as the transcription direction;
sequence regions on the
DNA strand having the same sequence as the RNA transcript that are 5' to the
5' end of the
RNA transcript are referred to as "upstream sequences;" sequence regions on
the DNA strand
having the same sequence as the RNA transcript that are 3' to the 3' end of
the RNA transcript
are referred to as "downstream sequences."
[0115] The term "control sequence" refers to a polynucleotide sequence that
can affect the
expression and processing of coding sequences to which it is ligated. The
nature of such
control sequences may depend upon the host organism. In particular
embodiments, control
sequences for prokaryotes may include a promoter, a ribosomal binding site,
and a
transcription termination sequence. For example, control sequences for
eukaryotes may
include promoters comprising one or a plurality of recognition sites for
transcription factors,
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transcription enhancer sequences, and transcription termination sequences.
"Control
sequences" can include leader sequences and/or fusion partner sequences.
[0116] The term "vector" means any molecule or entity (e.g., nucleic acid,
plasmid,
bacteriophage or virus) used to transfer protein coding information into a
host cell.
[0117] The term "expression vector" or "expression construct" refers to a
vector that is
suitable for transformation of a host cell and contains nucleic acid sequences
that direct
and/or control (in conjunction with the host cell) expression of one or more
heterologous
coding regions operatively linked thereto. An expression construct may
include, but is not
limited to, sequences that affect or control transcription, translation, and,
if introns are
present, affect RNA splicing of a coding region operably linked thereto.
[0118] As used herein, "operably linked" means that the components to which
the term is
applied are in a relationship that allows them to carry out their inherent
functions under
suitable conditions. For example, a control sequence in a vector that is
"operably linked" to a
protein coding sequence is ligated thereto so that expression of the protein
coding sequence is
achieved under conditions compatible with the transcriptional activity of the
control sequences.
[0119] The term "host cell" means a cell that has been transformed with a
nucleic acid
sequence and thereby expresses a gene of interest. The term includes the
progeny of the
parent cell, whether or not the progeny is identical in morphology or in
genetic make-up to
the original parent cell, so long as the gene of interest is present.
[0120] The terms "polypeptide" or "protein" are used interchangeably herein to
refer to a
polymer of amino acid residues. The terms also apply to amino acid polymers in
which one
or more amino acid residues is an analog or mimetic of a corresponding
naturally occurring
amino acid, as well as to naturally occurring amino acid polymers. The terms
can also
encompass amino acid polymers that have been modified, e.g., by the addition
of
carbohydrate residues to form glycoproteins, or phosphorylated. Polypeptides
and proteins
can be produced by a naturally-occurring and non-recombinant cell; or it is
produced by a
genetically-engineered or recombinant cell, and comprise molecules having the
amino acid
sequence of the native protein, or molecules having deletions from, additions
to, and/or
substitutions of one or more amino acids of the native sequence. The terms
"polypeptide" and
"protein" specifically encompass GIPR antigen binding proteins, antibodies, or
sequences
that have deletions from, additions to, and/or substitutions of one or more
amino acids of an
antigen-binding protein. The term "polypeptide fragment" refers to a
polypeptide that has an
amino-terminal deletion, a carboxyl-terminal deletion, and/or an internal
deletion as
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compared with the full-length protein. Such fragments may also contain
modified amino
acids as compared with the full-length protein. In certain embodiments,
fragments are about
five to 500 amino acids long. For example, fragments may be at least 5, 6, 8,
10, 14, 20, 50,
70, 100, 110, 150, 200, 250, 300, 350, 400, or 450 amino acids long. Useful
polypeptide
fragments include immunologically functional fragments of antibodies,
including binding
domains.
[0121] The term "isolated protein" means that a subject protein (1) is free of
at least some
other proteins with which it would normally be found, (2) is essentially free
of other proteins
from the same source, e.g., from the same species, (3) is expressed by a cell
from a different
species, (4) has been separated from at least about 50 percent of
polynucleotides, lipids,
carbohydrates, or other materials with which it is associated in nature, (5)
is operably
associated (by covalent or noncovalent interaction) with a polypeptide with
which it is not
associated in nature, or (6) does not occur in nature. Typically, an "isolated
protein"
constitutes at least about 5%, at least about 10%, at least about 25%, or at
least about 50% of
a given sample. Genomic DNA, cDNA, mRNA or other RNA, of synthetic origin, or
any
combination thereof may encode such an isolated protein. Preferably, the
isolated protein is
substantially free from proteins or polypeptides or other contaminants that
are found in its
natural environment that would interfere with its therapeutic, diagnostic,
prophylactic,
research or other use.
[0122] A "variant" of a polypeptide (e.g., an antigen binding protein such as
an antibody)
comprises an amino acid sequence wherein one or more amino acid residues are
inserted into,
deleted from and/or substituted into the amino acid sequence relative to
another polypeptide
sequence. Variants include fusion proteins.
[0123] A "derivative" of a polypeptide is a polypeptide (e.g., an antigen
binding protein such
as an antibody) that has been chemically modified in some manner distinct from
insertion,
deletion, or substitution variants, e.g., via conjugation to another chemical
moiety.
[0124] The term "naturally occurring" as used throughout the specification in
connection
with biological materials such as polypeptides, nucleic acids, host cells, and
the like, refers to
materials which are found in nature.
[0125] A "subject" or "patient" as used herein can be any mammal. In a typical
embodiment,
the subject or patient is a human.
[0126] As disclosed herein, a GIPR polypeptide described by the instant
disclosure can be
engineered and/or produced using standard molecular biology methodology. In
various
examples, a nucleic acid sequence encoding a GIPR, which can comprise all or a
portion of
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SEQ ID NOs: 1203, 1203 or 1205, can be isolated and/or amplified from genomic
DNA, or
cDNA using appropriate oligonucleotide primers. Primers can be designed based
on the
nucleic and amino acid sequences provided herein according to standard (RT)-
PCR
amplification techniques. The amplified GIPR nucleic acid can then be cloned
into a suitable
vector and characterized by DNA sequence analysis.
[0127] Oligonucleotides for use as probes in isolating or amplifying all or a
portion of the
GIPR sequences provided herein can be designed and generated using standard
synthetic
techniques, e.g., automated DNA synthesis apparatus, or can be isolated from a
longer
sequence of DNA.
[0128] The 466 amino acid sequence of human GIPR is (Volz et al., FEBS Lett.
373:23-29
(1995); NCBI Reference Sequence: NP 0001555):
[0129] MTTSPILQLL LRLSLCGLLL QRAETGSKGQ TAGELYQRWE RYRRECQETL
AAAEPPSGLA CNGSFDMYVC WDYAAPNATA RASCPWYLPW HHHVAAGFVL
RQCGSDGQWG LWRDHTQCEN PEKNEAFLDQ RLILERLQVM YTVGYSLSLA
TLLLALLILS LFRRLHCTRN YIHINLFTSF MLRAAAILSR DRLLPRPGPY
LGDQALALWN QALAACRTAQ IVTQYCVGAN YTWLLVEGVY LHSLLVLVGG
SEEGHFRYYL LLGWGAPALF VIPWVIVRYL YENTQCWERN EVKAIWWIIR
TPILMTILIN FLIFIRILGI LLSKLRTRQM RCRDYRLRLA RSTLTLVPLL
GVHEVVFAPV TEEQARGALR FAKLGFEIFL SSFQGFLVSV LYCFINKEVQ
SEIRRGWHHC RLRRSLGEEQ RQLPERAFRA LPSGSGPGEV PTSRGLSSGT
LPGPGNEASR ELESYC (SEQIDNO: 1201)
[0130] and is encoded by the DNA sequence (NCBI Reference Sequence: NM
000164):
[0131] ggcagcggtg gcaggggctg caggagcaag tgaccaggag caggactggg
gacaggcctg atcgcccctg cacgaaccag acccttcgcc gccctcacga
tgactacctc tccgatcctg cagctgctgc tgcggctctc actgtgcggg
ctgctgctcc agagggcgga gacaggctct aaggggcaga cggcggggga
gctgtaccag cgctgggaac ggtaccgcag ggagtgccag gagaccttgg
cagccgcgga accgccttca ggcctcgcct gtaacgggtc cttcgatatg
tacgtctgct gggactatgc tgcacccaat gccactgccc gtgcgtcctg
cccctggtac ctgccctggc accaccatgt ggctgcaggt ttcgtcctcc
gccagtgtgg cagtgatggc caatggggac tttggagaga ccatacacaa
tgtgagaacc cagagaagaa tgaggccttt ctggaccaaa ggctcatctt
ggagcggttg caggtcatgt acactgtcgg ctactccctg tctctcgcca
cactgctgct agccctgctc atcttgagtt tgttcaggcg gctacattgc
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actagaaact atatccacat caacctgttc acgtctttca tgctgcgagc
tgcggccatt ctcagccgag accgtctgct acctcgacct ggcccctacc
ttggggacca ggcccttgcg ctgtggaacc aggccctcgc tgcctgccgc
acggcccaga tcgtgaccca gtactgcgtg ggtgccaact acacgtggct
gctggtggag ggcgtctacc tgcacagtct cctggtgctc gtgggaggct
ccgaggaggg ccacttccgc tactacctgc tcctcggctg gggggccccc
gcgcttttcg tcattccctg ggtgatcgtc aggtacctgt acgagaacac
gcagtgctgg gagcgcaacg aagtcaaggc catttggtgg attatacgga
cccccatcct catgaccatc ttgattaatt tcctcatttt tatccgcatt
cttggcattc tcctgtccaa gctgaggaca cggcaaatgc gctgccggga
ttaccggctg aggctggctc gctccacgct gacgctggtg cccctgctgg
gtgtccacga ggtggtgttt gctcccgtga cagaggaaca ggcccggggc
gccctgcgct tcgccaagct cggctttgag atcttcctca gctccttcca
gggcttcctg gtcagcgtcc tctactgctt catcaacaag gaggtgcagt
cggagatccg ccgtggctgg caccactgcc gcctgcgccg cagcctgggc
gaggagcaac gccagctccc ggagcgcgcc ttccgggccc tgccctccgg
ctccggcccg ggcgaggtcc ccaccagccg cggcttgtcc tcggggaccc
tcccagggcc tgggaatgag gccagccggg agttggaaag ttactgctag
ggggcgggat ccccgtgtct gttcagttag catggattta ttgagtgcca
actgcgtgcc aggcccagta cggaggacgc tggggaaatg gtgaaggaaa
cagaaaaaag gtccctgccc ttctggagat gacaactgag tggggaaaac
agaccgtgaa cacaaaacat caagttccac acacgctatg gaatggttat
gaagggaagc gagaaggggg cctagggtgg tctgggaggc gtctccaagg
aggtgacact taagccatcc ccgaaagagg tgaaagagat cactttgggg
agagctggag aacaggattc taggcggaag cgatagcata ggcaaaggcc
cttgggcagg aaggcgctca gccttggctg gagtagaatt aagtcagagc
caacaggtgg ggagagacag agaagtgggc aggggcaccc aagttgggat
ttcatttcag gtgcattgga gattcttagg agtgtctctt gggggtaata
ttttattttt taaaaaatga ggat (SEQIDNO: 1202).
[0132] A 430 amino acid isoform of human GIPR (isoform X1), predicted by
automated
computational analysis, has the sequence (NCBI Reference Sequence XP
005258790):
[0133] MTTSPILQLL LRLSLCGLLL QRAETGSKGQ TAGELYQRWE RYRRECQETL
AAAEPPSVAA GFVLRQCGSD GQWGLWRDHT QCENPEKNEA FLDQRLILER
LQVMYTVGYS LSLATLLLAL LILSLFRRLH CTRNYIHINL FTSFMLRAAA
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ILSRDRLLPR PGPYLGDQAL ALWNQALAAC RTAQIVTQYC VGANYTWLLV
EGVYLHSLLV LVGGSEEGHF RYYLLLGWGA PALFVIPWVI VRYLYENTQC
WERNEVKAIW WIIRTPILMT ILINFLIFIR ILGILLSKLR TRQMRCRDYR
LRLARSTLTL VPLLGVHEVV FAPVTEEQAR GALRFAKLGF EIFLSSFQGF
LVSVLYCFIN KEVQSEIRRG WHHCRLRRSL GEEQRQLPER AFRALPSGSG
PGEVPTSRGL SSGTLPGPGN EASRELESYC(SEQIDNO: 1203)
[0134] and is encoded by the DNA sequence:
[0135] atgaccacca gcccgattct gcagctgctg ctgcgcctga gcctgtgcgg
cctgctgctg cagcgcgcgg aaaccggcag caaaggccag accgcgggcg
aactgtatca gcgctgggaa cgctatcgcc gcgaatgcca ggaaaccctg
gcggcggcgg aaccgccgag cgtggcggcg ggctttgtgc tgcgccagtg
cggcagcgat ggccagtggg gcctgtggcg cgatcatacc cagtgcgaaa
acccggaaaa aaacgaagcg tttctggatc agcgcctgat tctggaacgc
ctgcaggtga tgtataccgt gggctatagc ctgagcctgg cgaccctgct
gctggcgctg ctgattctga gcctgtttcg ccgcctgcat tgcacccgca
actatattca tattaacctg tttaccagct ttatgctgcg cgcggcggcg
attctgagcc gcgatcgcct gctgccgcgc ccgggcccgt atctgggcga
tcaggcgctg gcgctgtgga accaggcgct ggcggcgtgc cgcaccgcgc
agattgtgac ccagtattgc gtgggcgcga actatacctg gctgctggtg
gaaggcgtgt atctgcatag cctgctggtg ctggtgggcg gcagcgaaga
aggccatttt cgctattatc tgctgctggg ctggggcgcg ccggcgctgt
ttgtgattcc gtgggtgatt gtgcgctatc tgtatgaaaa cacccagtgc
tgggaacgca acgaagtgaa agcgatttgg tggattattc gcaccccgat
tctgatgacc attctgatta actttctgat ttttattcgc attctgggca
ttctgctgag caaactgcgc acccgccaga tgcgctgccg cgattatcgc
ctgcgcctgg cgcgcagcac cctgaccctg gtgccgctgc tgggcgtgca
tgaagtggtg tttgcgccgg tgaccgaaga acaggcgcgc ggcgcgctgc
gctttgcgaa actgggcttt gaaatttttc tgagcagctt tcagggcttt
ctggtgagcg tgctgtattg ctttattaac aaagaagtgc agagcgaaat
tcgccgcggc tggcatcatt gccgcctgcg ccgcagcctg ggcgaagaac
agcgccagct gccggaacgc gcgtttcgcg cgctgccgag cggcagcggc
ccgggcgaag tgccgaccag ccgcggcctg agcagcggca ccctgccggg
cccgggcaac gaagcgagcc gcgaactgga aagctattgc(SEQIDNO: 1204).
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[0136] A 493 amino acid isoform of human GIPR, produced by alternative
splicing, has the
sequence (Gremlich et al., Diabetes 44:1202-8 (1995); UniProtKB Sequence
Identifier:
P48546-2):
101371 MTTSPILQLL LRLSLCGLLL QRAETGSKGQ TAGELYQRWE RYRRECQETL
AAAEPPSGLA CNGSFDMYVC WDYAAPNATA RASCPWYLPW HHHVAAGFVL
RQCGSDGQWG LWRDHTQCEN PEKNEAFLDQ RLILERLQVM YTVGYSLSLA
TLLLALLILS LFRRLHCTRN YIHINLFTSF MLRAAAILSR DRLLPRPGPY
LGDQALALWN QALAACRTAQ IVTQYCVGAN YTWLLVEGVY LHSLLVLVGG
SEEGHFRYYL LLGWGAPALF VIPWVIVRYL YENTQCWERN EVKAIWWIIR
TPILMTILIN FLIFIRILGI LLSKLRTRQM RCRDYRLRLA RSTLTLVPLL
GVHEVVFAPV TEEQARGALR FAKLGFEIFL SSFQGFLVSV LYCFINKEVG
RDPAAAPALW RRRGTAPPLS AIVSQVQSEI RRGWHHCRLR RSLGEEQRQL
PERAFRALPS GSGPGEVPTS RGLSSGTLPG PGNEASRELE SYC(SEQIDNO: 1205)
[0138] and is encoded by the DNA sequence:
[0139] atgaccacca gcccgattct gcagctgctg ctgcgcctga gcctgtgcgg
cctgctgctg cagcgcgcgg aaaccggcag caaaggccag accgcgggcg
aactgtatca gcgctgggaa cgctatcgcc gcgaatgcca ggaaaccctg
gcggcggcgg aaccgccgag cggcctggcg tgcaacggca gctttgatat
gtatgtgtgc tgggattatg cggcgccgaa cgcgaccgcg cgcgcgagct
gcccgtggta tctgccgtgg catcatcatg tggcggcggg ctttgtgctg
cgccagtgcg gcagcgatgg ccagtggggc ctgtggcgcg atcataccca
gtgcgaaaac ccggaaaaaa acgaagcgtt tctggatcag cgcctgattc
tggaacgcct gcaggtgatg tataccgtgg gctatagcct gagcctggcg
accctgctgc tggcgctgct gattctgagc ctgtttcgcc gcctgcattg
cacccgcaac tatattcata ttaacctgtt taccagcttt atgctgcgcg
cggcggcgat tctgagccgc gatcgcctgc tgccgcgccc gggcccgtat
ctgggcgatc aggcgctggc gctgtggaac caggcgctgg cggcgtgccg
caccgcgcag attgtgaccc agtattgcgt gggcgcgaac tatacctggc
tgctggtgga aggcgtgtat ctgcatagcc tgctggtgct ggtgggcggc
agcgaagaag gccattttcg ctattatctg ctgctgggct ggggcgcgcc
ggcgctgttt gtgattccgt gggtgattgt gcgctatctg tatgaaaaca
cccagtgctg ggaacgcaac gaagtgaaag cgatttggtg gattattcgc
accccgattc tgatgaccat tctgattaac tttctgattt ttattcgcat
tctgggcatt ctgctgagca aactgcgcac ccgccagatg cgctgccgcg
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attatcgcct gcgcctggcg cgcagcaccc tgaccctggt gccgctgctg
ggcgtgcatg aagtggtgtt tgcgccggtg accgaagaac aggcgcgcgg
cgcgctgcgc tttgcgaaac tgggctttga aatttttctg agcagctttc
agggctttct ggtgagcgtg ctgtattgct ttattaacaa agaagtgggc
cgcgatccgg cggcggcgcc ggcgctgtgg cgccgccgcg gcaccgcgcc
gccgctgagc gcgattgtga gccaggtgca gagcgaaatt cgccgcggct
ggcatcattg ccgcctgcgc cgcagcctgg gcgaagaaca gcgccagctg
ccggaacgcg cgtttcgcgc gctgccgagc ggcagcggcc cgggcgaagt
gccgaccagc cgcggcctga gcagcggcac cctgccgggc ccgggcaacg
aagcgagccg cgaactggaa agctattgct aa (SEQ ID NO: 1206)
[0140] The 460 amino acid sequence of murine GIPR is (NCBI Reference Sequence:
NP 001074284; uniprotKB/Swiss-Prot Q0P543-1); see Vassilatis et al., PNAS USA
2003,
100:4903-4908.
[0141] MPLRLLLLLL WLWGLQWAET DSEGQTTTGE LYQRWEHYGQ ECQKMLETTE
PPSGLACNGS FDMYACWNYT AANTTARVSC PWYLPWFRQV SAGFVFRQCG
SDGQWGSWRD HTQCENPEKN GAFQDQTLIL ERLQIMYTVG YSLSLTTLLL
ALLILSLFRR LHCTRNYIHM NLFTSFMLRA AAILTRDQLL PPLGPYTGDQ
APTPWNQALA ACRTAQIMTQ YCVGANYTWL LVEGVYLHHL LVIVGRSEKG
HFRCYLLLGW GAPALFVIPW VIVRYLRENT QCWERNEVKA IWWIIRTPIL
ITILINFLIF IRILGILVSK LRTRQMRCPD YRLRLARSTL TLVPLLGVHE
VVFAPVTEEQ VEGSLRFAKL AFEIFLSSFQ GFLVSVLYCFINKEVQSEIRQ
GWRHRRLRLS LQEQRPRPHQ ELAPRAVPLS SACREAAVGN ALPSGMLHVP
GDEVLESYC (SEQ ID NO: 1207)
[0142] and is encoded by the DNA sequence (NCBI Reference Sequence: NM
001080815):
[0143] atgccgctgc gcctgctgct gctgctgctg tggctgtggg gcctgcagtg
ggcggaaacc gatagcgaag gccagaccac caccggcgaa ctgtatcagc
gctgggaaca ttatggccag gaatgccaga aaatgctgga aaccaccgaa
ccgccgagcg gcctggcgtg caacggcagc tttgatatgt atgcgtgctg
gaactatacc gcggcgaaca ccaccgcgcg cgtgagctgc ccgtggtatc
tgccgtggtt tcgccaggtg agcgcgggct ttgtgtttcg ccagtgcggc
agcgatggcc agtggggcag ctggcgcgat catacccagt gcgaaaaccc
ggaaaaaaac ggcgcgtttc aggatcagac cctgattctg gaacgcctgc
agattatgta taccgtgggc tatagcctga gcctgaccac cctgctgctg
gcgctgctga ttctgagcct gtttcgccgc ctgcattgca cccgcaacta
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tattcatatg aacctgttta ccagctttat gctgcgcgcg gcggcgattc
tgacccgcga tcagctgctg ccgccgctgg gcccgtatac cggcgatcag
gcgccgaccc cgtggaacca ggcgctggcg gcgtgccgca ccgcgcagat
tatgacccag tattgcgtgg gcgcgaacta tacctggctg ctggtggaag
gcgtgtatct gcatcatctg ctggtgattg tgggccgcag cgaaaaaggc
cattttcgct gctatctgct gctgggctgg ggcgcgccgg cgctgtttgt
gattccgtgg gtgattgtgc gctatctgcg cgaaaacacc cagtgctggg
aacgcaacga agtgaaagcg atttggtgga ttattcgcac cccgattctg
attaccattc tgattaactt tctgattttt attcgcattc tgggcattct
ggtgagcaaa ctgcgcaccc gccagatgcg ctgcccggat tatcgcctgc
gcctggcgcg cagcaccctg accctggtgc cgctgctggg cgtgcatgaa
gtggtgtttg cgccggtgac cgaagaacag gtggaaggca gcctgcgctt
tgcgaaactg gcgtttgaaa tttttctgag cagctttcag ggctttctgg
tgagcgtgct gtattgcttt attaacaaag aagtgcagag cgaaattcgc
cagggctggc gccatcgccg cctgcgcctg agcctgcagg aacagcgccc
gcgcccgcat caggaactgg cgccgcgcgc ggtgccgctg agcagcgcgt
gccgcgaagc ggcggtgggc aacgcgctgc cgagcggcat gctgcatgtg
ccgggcgatg aagtgctgga aagctattgc taa (SEQ ID NO: 1208)
[0144] A 230 amino acid isoform of murine GIPR, produced by alternative
splicing, has the
sequence (Gerhard et al., Genome Res, 14:2121-2127 (2004); NCBI Reference
Sequence:
AAI20674):
[0145] MPLRLLLLLL WLWGLQWAET DSEGQTTTGE LYQRWEHYGQ ECQKMLETTE
PPSGLACNGS FDMYACWNYT AANTTARVSC PWYLPWFRQV SAGFVFRQCG
SDGQWGSWRD HTQCENPEKN GAFQDQTLIL ERLQIMYTVG YSLSLTTLLL
ALLILSLFRR LHCTRNYIHM NLFTSFMLRA AAILTRDQLL PPLGPYTGDQ
APTPWNQVLH RLLPGGTKTF PIYFRTFPHH(SEQIDNO: 1209)
[0146] and is encoded by the DNA sequence:
[0147] atgccgctgc gcctgctgct gctgctgctg tggctgtggg gcctgcagtg
ggcggaaacc gatagcgaag gccagaccac caccggcgaa ctgtatcagc
gctgggaaca ttatggccag gaatgccaga aaatgctgga aaccaccgaa
ccgccgagcg gcctggcgtg caacggcagc tttgatatgt atgcgtgctg
gaactatacc gcggcgaaca ccaccgcgcg cgtgagctgc ccgtggtatc
tgccgtggtt tcgccaggtg agcgcgggct ttgtgtttcg ccagtgcggc
agcgatggcc agtggggcag ctggcgcgat catacccagt gcgaaaaccc
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ggaaaaaaac ggcgcgtttc aggatcagac cctgattctg gaacgcctgc
agattatgta taccgtgggc tatagcctga gcctgaccac cctgctgctg
gcgctgctga ttctgagcct gtttcgccgc ctgcattgca cccgcaacta
tattcatatg aacctgttta ccagctttat gctgcgcgcg gcggcgattc
tgacccgcga tcagctgctg ccgccgctgg gcccgtatac cggcgatcag
gcgccgaccc cgtggaacca ggtgctgcat cgcctgctgc cgggcggcac
caaaaccttt ccgatttatt ttcgcacctt tccgcatcat taa(SEQIDNO: 1210).
[0148] As stated herein, the term "GIPR polypeptide" encompasses naturally
occurring GIPR
polypeptide sequences, e.g., human amino acid sequences SEQ ID NOs: 1201, 1203
or 1205.
The term "GIPR polypeptide," however, also encompasses polypeptides comprising
an amino
acid sequence that differs from the amino acid sequence of a naturally
occurring GIPR
polypeptide sequence, e.g., SEQ ID NOs: 1201, 1203 or 1205, by one or more
amino acids,
such that the sequence is at least 85% identical to SEQ ID NOs: 1201, 1203 or
1205. GIPR
polypeptides can be generated by introducing one or more amino acid
substitutions, either
conservative or non-conservative and using naturally or non-naturally
occurring amino acids,
at particular positions of the GIPR polypeptide.
[0149] A "conservative amino acid substitution" can involve a substitution of
a native amino
acid residue (i.e., a residue found in a given position of the wild-type GIPR
polypeptide
sequence) with a nonnative residue (i.e., a residue that is not found in a
given position of the
wild-type GIPR polypeptide sequence) such that there is little or no effect on
the polarity or
charge of the amino acid residue at that position. Conservative amino acid
substitutions also
encompass non-naturally occurring amino acid residues that are typically
incorporated by
chemical peptide synthesis rather than by synthesis in biological systems.
These include
peptidomimetics, and other reversed or inverted forms of amino acid moieties.
[0150] Naturally occurring residues can be divided into classes based on
common side chain
properties:
[0151] (1) hydrophobic: norleucine, Met, Ala, Val, Leu, Ile;
[0152] (2) neutral hydrophilic: Cys, Ser, Thr;
[0153] (3) acidic: Asp, Glu;
[0154] (4) basic: Asn, Gln, His, Lys, Arg;
[0155] (5) residues that influence chain orientation: Gly, Pro; and
[0156] (6) aromatic: Trp, Tyr, Phe.
[0157] Additional groups of amino acids can also be formulated using the
principles
described in, e.g., Creighton (1984) PROTEINS: STRUCTURE AND MOLECULAR
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PROPERTIES (2d Ed. 1993), W.H. Freeman and Company. In some instances it can
be
useful to further characterize substitutions based on two or more of such
features (e.g.,
substitution with a "small polar" residue, such as a Thr residue, can
represent a highly
conservative substitution in an appropriate context).
[0158] Conservative substitutions can involve the exchange of a member of one
of these
classes for another member of the same class. Non-conservative substitutions
can involve the
exchange of a member of one of these classes for a member from another class.
[0159] Synthetic, rare, or modified amino acid residues having known similar
physiochemical properties to those of an above-described grouping can be used
as a
"conservative" substitute for a particular amino acid residue in a sequence.
For example, a D-
Arg residue may serve as a substitute for a typical L-Arg residue. It also can
be the case that a
particular substitution can be described in terms of two or more of the above
described
classes (e.g., a substitution with a small and hydrophobic residue means
substituting one
amino acid with a residue(s) that is found in both of the above-described
classes or other
synthetic, rare, or modified residues that are known in the art to have
similar physiochemical
properties to such residues meeting both definitions).
[0160] Nucleic acid sequences encoding a GIPR polypeptide provided herein,
including
those degenerate to SEQ ID NOs: 1201, 1203 or 1205, and those encoding
polypeptide
variants of SEQ ID NOs: 1201, 1203 or 1205 form other aspects of the instant
disclosure.
[0161] In order to express the GIPR nucleic acid sequences provided herein,
the appropriate
coding sequences, e.g., SEQ ID NOs: 1201, 1203 or 1205, can be cloned into a
suitable
vector and after introduction in a suitable host, the sequence can be
expressed to produce the
encoded polypeptide according to standard cloning and expression techniques,
which are
known in the art (e.g., as described in Sambrook, J., Fritsh, E. F., and
Maniatis, T. Molecular
Cloning: A Laboratory Manual 2nd, ed., Cold Spring Harbor Laboratory, Cold
Spring Harbor
Laboratory Press, Cold Spring Harbor, N.Y., 1989). The invention also relates
to such vectors
comprising a nucleic acid sequence according to the invention.
[0162] A "vector" refers to a delivery vehicle that (a) promotes the
expression of a
polypeptide-encoding nucleic acid sequence; (b) promotes the production of the
polypeptide
therefrom; (c) promotes the transfection/transformation of target cells
therewith; (d) promotes
the replication of the nucleic acid sequence; (e) promotes stability of the
nucleic acid; (0
promotes detection of the nucleic acid and/or transformed/transfected cells;
and/or (g)
otherwise imparts advantageous biological and/or physiochemical function to
the
polypeptide-encoding nucleic acid. A vector can be any suitable vector,
including
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chromosomal, non-chromosomal, and synthetic nucleic acid vectors (a nucleic
acid sequence
comprising a suitable set of expression control elements). Examples of such
vectors include
derivatives of SV40, bacterial plasmids, phage DNA, baculovirus, yeast
plasmids, vectors
derived from combinations of plasmids and phage DNA, and viral nucleic acid
(RNA or
DNA) vectors.
[0163] A recombinant expression vector can be designed for expression of a
GIPR protein in
prokaryotic (e.g., E. coli) or eukaryotic cells (e.g., insect cells, using
baculovirus expression
vectors, yeast cells, or mammalian cells). In one embodiment the host cell is
a mammalian,
non-human host cell. Representative host cells include those hosts typically
used for cloning
and expression, including Escherichia coli strains TOP1OF', TOP10, DH10B,
DH5a, HB101,
W3110, BL21(DE3) and BL21 (DE3)pLysS, BLUESCRIPT (Stratagene), mammalian cell
lines CHO, CHO-K1, HEK293, 293-EBNA pIN vectors (Van Heeke & Schuster, J.
Biol.
Chem. 264: 5503-5509 (1989); pET vectors (Novagen, Madison Wis.).
Alternatively, the
recombinant expression vector can be transcribed and translated in vitro, for
example using
T7 promoter regulatory sequences and T7 polymerase and an in vitro translation
system.
Preferably, the vector contains a promoter upstream of the cloning site
containing the nucleic
acid sequence encoding the polypeptide. Examples of promoters, which can be
switched on
and off, include the lac promoter, the T7 promoter, the trc promoter, the tac
promoter and the
trp promoter.
[0164] Thus, provided herein are vectors comprising a nucleic acid sequence
encoding GIPR
that facilitate the expression of recombinant GIPR. In various embodiments,
the vectors
comprise an operably linked nucleotide sequence which regulates the expression
of GIPR. A
vector can comprise or be associated with any suitable promoter, enhancer, and
other
expression-facilitating elements. Examples of such elements include strong
expression
promoters (e.g., a human CMV IE promoter/enhancer, an RSV promoter, 5V40
promoter,
5L3-3 promoter, MMTV promoter, or HIV LTR promoter, EFlalpha promoter, CAG
promoter), effective poly (A) termination sequences, an origin of replication
for plasmid
product in E. coli, an antibiotic resistance gene as a selectable marker,
and/or a convenient
cloning site (e.g., a polylinker). Vectors also can comprise an inducible
promoter as opposed
to a constitutive promoter such as CMV IE. In one aspect, a nucleic acid
comprising a
sequence encoding a GIPR polypeptide which is operatively linked to a tissue
specific
promoter which promotes expression of the sequence in a metabolically-relevant
tissue, such
as liver or pancreatic tissue is provided.
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[0165] In another aspect of the instant disclosure, host cells comprising the
GIPR nucleic
acids and vectors disclosed herein are provided. In various embodiments, the
vector or
nucleic acid is integrated into the host cell genome, which in other
embodiments the vector or
nucleic acid is extra-chromosomal.
[0166] Recombinant cells, such as yeast, bacterial (e.g., E. coli), and
mammalian cells (e.g.,
immortalized mammalian cells) comprising such a nucleic acid, vector, or
combinations of
either or both thereof are provided. In various embodiments cells comprising a
non-integrated
nucleic acid, such as a plasmid, cosmid, phagemid, or linear expression
element, which
comprises a sequence coding for expression of a GIPR polypeptide, are
provided.
[0167] A vector comprising a nucleic acid sequence encoding a GIPR polypeptide
provided
herein can be introduced into a host cell by transformation or by
transfection. Methods of
transforming a cell with an expression vector are well known.
[0168] A GIPR-encoding nucleic acid can be positioned in and/or delivered to a
host cell or
host animal via a viral vector. Any suitable viral vector can be used in this
capacity. A viral
vector can comprise any number of viral polynucleotides, alone or in
combination with one
or more viral proteins, which facilitate delivery, replication, and/or
expression of the nucleic
acid of the invention in a desired host cell. The viral vector can be a
polynucleotide
comprising all or part of a viral genome, a viral protein/nucleic acid
conjugate, a virus-like
particle (VLP), or an intact virus particle comprising viral nucleic acids and
a GIPR
polypeptide-encoding nucleic acid. A viral particle viral vector can comprise
a wild-type viral
particle or a modified viral particle. The viral vector can be a vector which
requires the
presence of another vector or wild-type virus for replication and/or
expression (e.g., a viral
vector can be a helper-dependent virus), such as an adenoviral vector
amplicon. Typically,
such viral vectors consist of a wild-type viral particle, or a viral particle
modified in its
protein and/or nucleic acid content to increase transgene capacity or aid in
transfection and/or
expression of the nucleic acid (examples of such vectors include the herpes
virus/AAV
amplicons). Typically, a viral vector is similar to and/or derived from a
virus that normally
infects humans. Suitable viral vector particles in this respect, include, for
example, adenoviral
vector particles (including any virus of or derived from a virus of the
adenoviridae), adeno-
associated viral vector particles (AAV vector particles) or other parvoviruses
and parvoviral
vector particles, papillomaviral vector particles, flaviviral vectors,
alphaviral vectors, herpes
viral vectors, pox virus vectors, retroviral vectors, including lentiviral
vectors.
[0169] A GIPR polypeptide expressed as described herein can be isolated using
standard
protein purification methods. A GIPR polypeptide can be isolated from a cell
in which is it
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naturally expressed or it can be isolated from a cell that has been engineered
to express GIPR,
for example a cell that does not naturally express GIPR.
[0170] Protein purification methods that can be employed to isolate a GIPR
polypeptide, as
well as associated materials and reagents, are known in the art. Additional
purification
methods that may be useful for isolating a GIPR polypeptide can be found in
references such
as Bootcov MR, 1997, Proc. Natl. Acad. Sci. USA 94:11514-9, Fairlie WD, 2000,
Gene 254:
67-76.
[0171] Antagonist antigen binding proteins that bind GIPR, including human
GIPR (hGIPR)
are provided herein. In one embodiment, the human GIPR has the sequence as
such as set
forth in SEQ ID NO: 1201. In another embodiment, the human GIPR has the
sequence as
such set forth in SEQ ID NO: 1203. In another embodiment, the human GIPR has
the
sequence as such set forth in SEQ ID NO: 1205.
[0172] The antigen binding proteins provided are polypeptides into which one
or more
complementary determining regions (CDRs), as described herein, are embedded
and/or
joined. In some antigen binding proteins, the CDRs are embedded into a
"framework" region,
which orients the CDR(s) such that the proper antigen binding properties of
the CDR(s) are
achieved. Certain antigen binding proteins described herein are antibodies or
are derived
from antibodies. In other antigen binding proteins, the CDR sequences are
embedded in a
different type of protein scaffold. The various structures are further
described below.
[0173] The antigen binding proteins that are disclosed herein have a variety
of utilities. The
antigen binding proteins, for instance, are useful in specific binding assays,
affinity
purification of GIPR, and in screening assays to identify other antagonists of
GIPR activity.
Other uses for the antigen binding proteins include, for example, diagnosis of
GIPR-
associated diseases or conditions and screening assays to determine the
presence or absence
of GIPR. Given that the antigen binding proteins that are provided are
antagonists, the GIPR
antigen binding proteins have value in therapeutic methods in which it is
useful to reduce
weight gain, even while maintaining or increasing food intake, increasing %
fat mass and
increasing % lean mass, improving glucose tolerance, decreasing insulin
levels, decreasing
cholesterol and triglyceride levels. Accordingly, the antigen binding proteins
have utility in
the treatment and prevention of diabetes, e.g., type 2 diabetes, obesity,
dyslipidemia, elevated
glucose levels or elevated insulin levels.
[0174] A variety of selective binding agents useful for modulating the
activity of GIPR are
provided. These agents include, for instance, antigen binding proteins that
contain an antigen
binding domain (e.g., scFvs, domain antibodies, and polypeptides with an
antigen binding
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region) and specifically bind to a GIPR polypeptide, in particular human GIPR.
Some of the
agents, for example, are useful in enhancing the activity of GIPR, and can
activate one or
more activities associated with GIPR.
[0175] In general the antigen binding proteins that are provided typically
comprise one or
more CDRs as described herein (e.g., 1, 2, 3, 4, 5 or 6). In some instances,
the antigen
binding protein comprises (a) a polypeptide structure and (b) one or more CDRs
that are
inserted into and/or joined to the polypeptide structure. The polypeptide
structure can take a
variety of different forms. For example, it can be, or comprise, the framework
of a naturally
occurring antibody, or fragment or variant thereof, or may be completely
synthetic in nature.
Examples of various polypeptide structures are further described below.
[0176] In certain embodiments, the polypeptide structure of the antigen
binding proteins is an
antibody or is derived from an antibody. Accordingly, examples of certain
antigen binding
proteins that are provided include, but are not limited to, monoclonal
antibodies, bispecific
antibodies, minibodies, domain antibodies such as Nanobodies0, synthetic
antibodies
(sometimes referred to herein as "antibody mimetics"), chimeric antibodies,
humanized
antibodies, human antibodies, antibody fusions, and portions or fragments of
each,
respectively. In some instances, the antigen binding protein is an
immunological fragment of
a complete antibody (e.g., a Fab, a Fab', a F(ab')2). In other instances the
antigen binding
protein is a scFv that uses CDRs from an antibody of the present invention.
[0177] The antigen binding proteins as provided herein specifically bind to a
human GIPR. In
a specific embodiment, the antigen binding protein specifically binds to human
GIPR
comprising or consisting of the amino acid sequence of SEQ ID NO: 1201. In a
specific
embodiment, the antigen binding protein specifically binds to human GIPR
comprising or
consisting of the amino acid sequence of SEQ ID NO: 1203. In a specific
embodiment, the
antigen binding protein specifically binds to human GIPR comprising or
consisting of the
amino acid sequence of SEQ ID NO: 1205.
[0178] The antigen binding proteins that are provided are antagonists and
typically have one,
two, three, four, five, six, seven or all eight of the following
characteristics:
[0179] (a) ability to prevent or reduce binding of GIP to GIPR, where the
levels can be
measured, for example, by the methods such as radioactive- or fluorescence-
labeled ligand
binding study, or by the methods described herein (e.g. cAMP assay or other
functional
assays). The decrease can be at least 10, 25, 50, 100% or more relative to the
pre-treatment
levels of SEQ ID NO: 1201, 1203 or 1205 under comparable conditions.
[0180] (b) ability to decrease blood glucose;
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[0181] (c) ability to increase glucose tolerance;
[0182] (d) ability to increase insulin sensitivity;
[0183] (e) ability to decrease body weight or reduce body weight gain;
[0184] (f) ability to decrease fat mass or decrease inflammation in fat
tissue;
[0185] (g) ability to decrease fasting insulin levels;
[0186] (h) ability to decrease circulating cholesterol levels;
[0187] (i) ability to decrease circulating triglyceride levels;
[0188] (j) ability to decrease liver steatosis or reduce triglyceride level
in liver;
[0189] (k) ability to decrease AST, ALT, and/or ALP levels.
[0190] In one embodiment, a GIPR antigen binding protein has one or more of
the
following activities:
[0191] (a) binds human GIPR such that KD is <200 nM, is <150 nM, is <100 nM
, is <50
nM, is <10 nM, is <5 nM, is <2 nM, or is <1 nM, e.g., as measured via a
surface plasma
resonance or kinetic exclusion assay technique.
[0192] (b) has a half-life in human serum of at least 3 days;
[0193] Some antigen binding proteins that are provided have an on-rate (ka)
for GIPR of at
least 104/ M x seconds, at least 105/M x seconds, or at least 106/M x seconds
as measured, for
instance, as described below. Certain antigen binding proteins that are
provided have a slow
dissociation rate or off-rate. Some antigen binding proteins, for instance,
have a kd (off-rate)
of lx 10-2 s-1 , or lx 10-3 s-1, or lx 10-4 s-1 , or lx 10-5 s-1 . In certain
embodiments, the
antigen binding protein has a KD (equilibrium binding affinity) of less than
25 pM, 50 pM,
100 pM, 500 pM, 1 nM, 5 nM, 10 nM, 25 nM or 50 nM.
[0194] Depending on the assay, the binding of an antigen binding protein to
its target can
also be measured as an EC50 (the concentration of antigen binding protein that
gives a half-
maximal response when bound to target). An EC50 for an anti-GIPR antigen
binding protein
of the present invention can be determined by incubating different
concentrations of antigen
binding protein with cells expressing GIPR. Anti-GIPR antigen binding proteins
of the
present invention can have EC5Os less 200 nM, 150nM, 125 nM, 100 nM, 90 nM, 80
nM, 70
nM, 60 nM, 50 nM, 40 nM, or 30 nM.
[0195] An IC50 (the half maximal inhibitory concentration: a measure of the
effectiveness of
an antigen binding protein in inhibiting a specific biological or biochemical
function) can
also be used to measure the activity of anti-GIPR antigen binding protein. An
IC 50 can be
measured using a functional assay. For example, such an assay can be used for
the
quantitative determination of cAMP in HEK 293T cells expressing the human GIPR
or
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cynomolgus monkey GIPR. GIP binding causes GIPR conformation change,
stimulating the
G protein to active adenylate cyclase resulting in cAMP production from ATP.
Antibody
binding to GIPR prevents GIP binding to GIPR with the result being less cAMP.
This is
measurable by a cAMP assay. Anti-GIPR antigen binding proteins of the present
invention
can have IC50s less 200 nM, 150nM, 125 nM, 100 nM, 90 nM, 80 nM, 70 nM, 60 nM,
50
nM, 40 nM, 30 nM, 29 nM, 28 nM, 27 nM, 26 nM, 25 nM, 24 nM, 23 nM, 22 nM, 21
mM,
20 nM, 19 nM, 18 nM, 17 nM, 16 nM, 15 nM, 14 nM, 13 nM, 12 nM, 11 mM, 10 nM, 9
nM,
8 nM, 7 nM, 6 nM, 5 nM, 4 nM, 3 nM, 2 nM, or 1 nM.
[0196] In another aspect, an antigen-binding protein is provided having a half-
life of at least
one day in vitro or in vivo (e.g., when administered to a human subject). In
one embodiment,
the antigen binding protein has a half-life of at least three days. In various
other
embodiments, the antigen binding protein has a half-life of 4, 5, 6, 7, 8,9,
10, 15, 20, 25, 30,
40, 50, or 60 days or longer. In another embodiment, the antigen binding
protein is
derivatized or modified such that it has a longer half-life as compared to the
underivatized or
unmodified antibody. In another embodiment, the antigen binding protein
contains point
mutations to increase serum half-life. Further details regarding such mutant
and derivatized
forms are provided below.
[0197] Some of the antigen binding proteins that are provided have the
structure typically
associated with naturally occurring antibodies. The structural units of these
antibodies
typically comprise one or more tetramers, each composed of two identical
couplets of
polypeptide chains, though some species of mammals also produce antibodies
having only a
single heavy chain. In a typical antibody, each pair or couplet includes one
full-length "light"
chain (in certain embodiments, about 25 kDa) and one full-length "heavy" chain
(in certain
embodiments, about 50-70 kDa). Each individual immunoglobulin chain is
composed of
several "immunoglobulin domains", each consisting of roughly 90 to 110 amino
acids and
expressing a characteristic folding pattern. These domains are the basic units
of which
antibody polypeptides are composed. The amino-terminal portion of each chain
typically
includes a variable domain that is responsible for antigen recognition. The
carboxy-terminal
portion is more conserved evolutionarily than the other end of the chain and
is referred to as
the "constant region" or "C region". Human light chains generally are
classified as kappa and
lambda light chains, and each of these contains one variable domain and one
constant
domain. Heavy chains are typically classified as mu, delta, gamma, alpha, or
epsilon chains,
and these define the antibody's isotype as IgM, IgD, IgG, IgA, and IgE,
respectively. IgG has
several subtypes, including, but not limited to, IgGl, IgG2, IgG3, and IgG4.
IgM subtypes
39
CA 03062194 2019-10-31
WO 2018/237097
PCT/US2018/038638
include IgM, and IgM2. IgA subtypes include IgAl and IgA2. In humans, the IgA
and IgD
isotypes contain four heavy chains and four light chains; the IgG and IgE
isotypes contain
two heavy chains and two light chains; and the IgM isotype contains five heavy
chains and
five light chains. The heavy chain C region typically comprises one or more
domains that
may be responsible for effector function. The number of heavy chain constant
region domains
will depend on the isotype. IgG heavy chains, for example, each contain three
C region
domains known as CHL CH2 and CH3. The antibodies that are provided can have
any of
these isotypes and subtypes. In certain embodiments, the GIPR antibody is of
the IgGl, IgG2,
or IgG4 subtype. The terms "GIPR antibody" and "anti-GIPR antibody" are used
interchangeably throughout this application and figures. Both terms refer to
an antibody that
binds to GIPR.
[0198] In full-length light and heavy chains, the variable and constant
regions are joined by a
"J" region of about twelve or more amino acids, with the heavy chain also
including a "D"
region of about ten more amino acids. See, e.g. Fundamental Immunology, 2nd
ed., Ch. 7
(Paul, W., ed.) 1989, New York: Raven Press (hereby incorporated by reference
in its entirety
for all purposes). The variable regions of each light/heavy chain pair
typically form the
antigen binding site.
[0199] For the antibodies provided herein, the variable regions of
immunoglobulin chains
generally exhibit the same overall structure, comprising relatively conserved
framework
regions (FR) joined by three hypervariable regions, more often called
"complementarity
determining regions" or CDRs. The CDRs from the two chains of each heavy
chain/light
chain pair mentioned above typically are aligned by the framework regions to
form a
structure that binds specifically with a specific epitope on GIPR. From N-
terminal to C-
terminal, naturally-occurring light and heavy chain variable regions both
typically conform
with the following order of these elements: FR1, CDR1, FR2, CDR2, FR3, CDR3
and FR4.
A numbering system has been devised for assigning numbers to amino acids that
occupy
positions in each of these domains. This numbering system is defined in Kabat
Sequences of
Proteins of Immunological Interest (1987 and 1991, NIH, Bethesda, Md.), or
Chothia &
Lesk, 1987, J. Mol. Biol. 196:901-917; Chothia et al., 1989, Nature 342:878-
883.
[0200] The sequence information for specific antibodies prepared and
identified as described
in the Examples below is summarized in TABLE 1. Thus, in an embodiment, an
antigen
binding protein is an antibody with the CDR, variable domain and light and
heavy chain
sequences as specified in one of the rows of TABLE 1.
CA 03062194 2019-10-31
WO 2018/237097
PCT/US2018/038638
[0201] SEQ ID NOs have been assigned to variable light chain, variable heavy
chain, light
chain, heavy chain, CDRL1, CDRL2, CDRL3, CDRH1, CDRH2, and CDRH3 sequences of
the antibodies and fragments thereof of the present invention and are shown in
TABLE 1.
SEQ ID NOs have also been assigned to polynucleotides encoding the variable
light chain,
variable heavy chain, light chain, heavy chain, CDRL1, CDRL2, CDRL3, CDRH1,
CDRH2,
and CDRH3 sequences of the antibodies and fragments thereof of the present
invention and
are shown in TABLE 2. The antigen binding proteins of the present invention
can be
identified by SEQ ID NO, but also by construct name (e.g., 2C2.005) or
identifier number
(e.g., iPS:336175). The antigen binding proteins identified in Tables 1-5
below can be
grouped into families based on construct name. For example, the "4B1 family"
includes the
constructs 4B1, 4B1.010, 4B1.011, 4B1.012, 4B1.013, 4B1.014, 4B1.015, and
4B1.016.
[0202] The various light chain and heavy chain variable regions provided
herein are depicted
in TABLE 3. Each of these variable regions may be attached to a heavy or light
chain
constant regions to form a complete antibody heavy and light chain,
respectively.
Furthermore, each of the so generated heavy and light chain sequences may be
combined to
form a complete antibody structure.
41
A-2164-WO-PCT
Table 1. Amino acid SEQ ID NOs.
Construct VL VII LC HC CDRL1 CDRL2 CDRL3 CDRH1 CDRH2 CDRH3
0
n.)
2G10.303 723 724 963 964 4 5 6 364 365
366 =
2G10.304 727 728 967 968 10 11 12 370 371
372 0 e
2G10.323 731 732 971 972 16 17 18 376 377
378 c +4
-4
2G10.309 735 736 975 976 22 23 24 382 383
384 =
o
2G10.316 739 740 979 980 28 29 30 388 389
390 -4
2G10.604 743 744 983 984 34 35 36 394 395
396
2G10.609 747 748 987 988 40 41 42 400 401
402
2G10.603 751 752 991 992 46 47 48 406 407
408
2G10.318 755 756 995 996 52 53 54 412 413
414
2G10.324 759 760 999 1000 58 59 60 418 419
420
2G10.322 763 764 1003 1004 64 65 66 424 425
426
2G10.315 767 768 1007 1008 70 71 72 430 431
432
2G10.331 771 772 1011 1012 76 77 78 436 437
438
2G10.320 775 776 1015 1016 82 83 84 442 443
444 P
2G10.328 779 780 1019 1020 88 89 90 448 449
450
2G10.333 783 784 1023 1024 94 95 96 454 455
456
2G10.301 787 788 1027 1028 100 101 102 460 461
462 .
2G10.601 791 792 1031 1032 106 107 108 466 467
468
0
2G10.326 795 796 1035 1036 112 113 114 472 473
474
2G10.308 799 800 1039 1040 118 119 120 478 479
480
2G10.608 803 804 1043 1044 124 125 126 484 485
486
2G10.336 807 808 1047 1048 130 131 132 490 491
492
2G10.344 811 812 1051 1052 136 137 138 496 497
498
2G10.310 815 816 1055 1056 142 143 144 502 503
504
2G10.610 819 820 1059 1060 148 149 150 508 509
510
2G10.312 823 824 1063 1064 154 155 156 514 515
516
2G10.329 827 828 1067 1068 160 161 162 520 521
522
2G10.327 831 832 1071 1072 166 167 168 526 527
528
1 V
2G10.338 835 836 1075 1076 172 173 174 532 533
534 n
2G10.314 839 840 1079 1080 178 179 180 538 539
540 1-3
2G10.337 843 844 1083 1084 184 185 186 544 545
546
n.)
2G10.341 847 848 1087 1088 190 191 192 550 551
552 o
2G10.302 851 852 1091 1092 196 197 198 556 557
558 oe
-a-,
2G10.602 855 856 1095 1096 202 203 204 562 563
564
oe
2G10.325 859 860 1099 1100 208 209 210 568 569
570 o
oe
42
A-2164-WO-PCT
2G10.343 863 864 1103 1104 214 215 216 574 575
576
2G10.313 867 868 1107 1108 220 221 222 580 581
582
2G10.317 871 872 1111 1112 226 227 228 586 587
588 -- 0
2G10.311 875 876 1115 1116 232 233 234 592 593
594 -- n.)
o
2G10.306 879 880 1119 1120 238 239 240 598 599
600
oe
2G10.606 883 884 1123 1124 244 245 246 604 605
606 -- t:1
2G10.347 887 888 1127 1128 250 251 252 610 611
612 --.1
o
2G10.348 891 892 1131 1132 256 257 258 616 617
618
--.1
2G10.346 895 896 1135 1136 262 263 264 622 623
624
2G10.647 899 900 1139 1140 268 269 270 628 629
630
2G10.649 903 904 1143 1144 274 275 276 634 635
636
2G10.305 907 908 1147 1148 280 281 282 640 641
642
2G10.605 911 912 1151 1152 286 287 288 646 647
648
2G10.340 915 916 1155 1156 292 293 294 652 653
654
2G10.334 919 920 1159 1160 298 299 300 658 659
660
2G10.339 923 924 1163 1164 304 305 306 664 665
666
2G10.307 927 928 1167 1168 310 311 312 670 671
672 Q
2G10.607 931 932 1171 1172 316 317 318 676 677
678 -- 0
,..
2G10.321 935 936 1175 1176 322 323 324 682 683
684 .
N,
,
2G10.342 939 940 1179 1180 328 329 330 688 689
690 -- .
2G10.319 943 944 1183 1184 334 335 336 694 695
696 -- ^,
2G10.332 947 948 1187 1188 340 341 342 700 701
702 -- ,
,
2G10.345 951 952 1191 1192 346 347 348 706 707
708 -- ,
0
,
2G10.335 955 956 1195 1196 352 353 354 712 713
714 -- ,..
,
2G10.330 959 960 1199 1200 358 359 360 718 719
720
iPS:529381 1286 1287 1288 1289 1290 1291 1292 1293 1294 1295
iPS:529382 1296 1297 1298 1299 1300 1301 1302 1303 1304 1305
iPS:529397 1306 1307 1308 1309 1310 1311 1312 1313
1314 1315
iPS:529399 1316 1317 1318 1319 1320 1321 1322 1323
1324 1325
iPS:529400 1326 1327 1328 1329 1330 1331 1332 1333
1334 1335
iPS:529403 1336 1337 1338 1339 1340 1341 1342 1343
1344 1345 IV
n
iPS:529404 1346 1347 1348 1349 1350 1351 1352 1353
1354 1355 1-3
iPS:529405 1356 1357 1358 1359 1360 1351 1352 1353
1354 1355
cp
n.)
o
1-,
oe
-1
oe
cA
oe
43
A-2164-WO-PCT
Table 2. Nucleic acid SEQ ID NOs.
Construct VL VII LC HC CDRL1 CDRL2 CDRL3 CDRH1 CDRH2 CDRH3
0
n.)
2G10.303 721 722 961 962 1 2 3 361 362
363 =
2G10.304 725 726 965 966 7 8 9 367 368
369 ce 0
2G10.323 729 730 969 970 13 14 15 373 374
375
-4
2G10.309 733 734 973 974 19 20 21 379 380
381 =
o
2G10.316 737 738 977 978 25 26 27 385 386
387 -4
2G10.604 741 742 981 982 31 32 33 391 392
393
2G10.609 745 746 985 986 37 38 39 397 398
399
2G10.603 749 750 989 990 43 44 45 403 404
405
2G10.318 753 754 993 994 49 50 51 409 410
411
2G10.324 757 758 997 998 55 56 57 415 416
417
2G10.322 761 762 1001 1002 61 62 63 421 422
423
2G10.315 765 766 1005 1006 67 68 69 427 428
429
2G10.331 769 770 1009 1010 73 74 75 433 434
435
2G10.320 773 774 1013 1014 79 80 81 439 440
441 P
2G10.328 777 778 1017 1018 85 86 87 445 446
447
2G10.333 781 782 1021 1022 91 92 93 451 452
453
2G10.301 785 786 1025 1026 97 98 99 457 458
459 .
2G10.601 789 790 1029 1030 103 104 105 463 464
465
0
2G10.326 793 794 1033 1034 109 110 111 469 470
471
2G10.308 797 798 1037 1038 115 116 117 475 476
477
2G10.608 801 802 1041 1042 121 122 123 481 482
483
2G10.336 805 806 1045 1046 127 128 129 487 488
489
2G10.344 809 810 1049 1050 133 134 135 493 494
495
2G10.310 813 814 1053 1054 139 140 141 499 500
501
2G10.610 817 818 1057 1058 145 146 147 505 506
507
2G10.312 821 822 1061 1062 151 152 153 511 512
513
2G10.329 825 826 1065 1066 157 158 159 517 518
519
2G10.327 829 830 1069 1070 163 164 165 523 524
525
1 V
2G10.338 833 834 1073 1074 169 170 171 529 530
531 n
2G10.314 837 838 1077 1078 175 176 177 535 536
537 1-3
2G10.337 841 842 1081 1082 181 182 183 541 542
543 ci )
n.)
2G10.341 845 846 1085 1086 187 188 189 547 548
549 o
2G10.302 849 850 1089 1090 193 194 195 553 554
555 cee
-a-,
2G10.602 853 854 1093 1094 199 200 201 559 560
561
cio
2G10.325 857 858 1097 1098 205 206 207 565 566
567 o
o o
44
A-2164-WO-PCT
2G10.343 861 862 1101 1102 211 212 213 571 572
573
2G10.313 865 866 1105 1106 217 218 219 577 578
579
2G10.317 869 870 1109 1110 223 224 225 583 584
585 0
2G10.311 873 874 1113 1114 229 230 231 589 590
591 n.)
o
2G10.306 877 878 1117 1118 235 236 237 595 596
597
oe
2G10.606 881 882 1121 1122 241 242 243 601 602
603 t:1
2G10.347 885 886 1125 1126 247 248 249 607 608
609 --.1
o
2G10.348 889 890 1129 1130 253 254 255 613 614
615
--.1
2G10.346 893 894 1133 1134 259 260 261 619 620
621
2G10.647 897 898 1137 1138 265 266 267 625 626
627
2G10.649 901 902 1141 1142 271 272 273 631 632
633
2G10.305 905 906 1145 1146 277 278 279 637 638
639
2G10.605 909 910 1149 1150 283 284 285 643 644
645
2G10.340 913 914 1153 1154 289 290 291 649 650
651
2G10.334 917 918 1157 1158 295 296 297 655 656
657
2G10.339 921 922 1161 1162 301 302 303 661 662
663
2G10.307 925 926 1165 1166 307 308 309 667 668
669 P
2G10.607 929 930 1169 1170 313 314 315 673 674
675 0
,..
2G10.321 933 934 1173 1174 319 320 321 679 680
681 0
r.,
2G10.342 937 938 1177 1178 325 326 327 685 686
687 ,
2G10.319 941 942 1181 1182 331 332 333 691 692
693
0
2G10.332 945 946 1185 1186 337 338 339 697 698
699 ,
,
2G10.345 949 950 1189 1190 343 344 345 703 704
705 ,
0
,
2G10.335 953 954 1193 1194 349 350 351 709 710
711 ,..
,
2G10.330 957 958 1197 1198 355 356 357 715 716
717
iPS:529381 1377 1378 1361 1362
iPS:529382 1379 1380 1363 1364
iPS:529397 1381 1382 1365 1366
iPS:529399 1383 1384 1367 1368
iPS:529400 1385 1386 1369 1370
iPS:529403 1387 1388 1371 1372
IV
n
iPS:529404 1389 1390 1373
1374 1-3
iPS:529405 1391 1392 1375 1376
cp
n.)
o
1-,
oe
CO-
c,.)
oe
o
c,.)
oe
A-2164-WO-PCT
Table 3. Exemplary Variable Light and Variable Heavy Regions: Nucleic Acid
("NA") and Amino Acid ("AA") Sequences
0
k:AwTypeggaggagnmaggkeNNitokititimagnmaggnmaaaognagammognitWANtogiottomonamognm
na cao
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGT
GTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGG CCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGC
GCCAGTCAGAGTGTTGATAGACACTTAGCCTGGTAC ATCTGGATTCACCTTCAGTAACTATGGCATGCACTG
CAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATC GGTCCGCCAGGCTCCAGGCGAGGGGCTGGAGTGGG
TACGAAGCAGCCACCAGGGCCACTGGTATCCCAGC TGGCAGCTATATGGTTTGATGCAAGTGATAAATACT
CAGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCAC ATGCAGACGCCGTGAAGGGCCGATTCACCATCTCCA
NA TCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGC GAGACAACTCCAAGAACACGCTGTATCTGCAAATG
AGTTTATTACTGTCAGCAGTATCAGAACTGGCCTCT AACAGCCTGAGAGCCGAGGACACGGCTGTGTATTA
CACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA CTGTGCGAGAGATTTGGCGATTTTTGGAGTGGTCCC
CGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTC
TAGT
(SEQ ID NO: 721) (SEQ ID NO: 722)
EIVMTQ SP ATL SV SP GERATL SCRASQ SVDRHLAWYQ QVQLVE SGGGVVQPGRSLRL
SCAASGFTFSNYGMHW
QKP GQAPRLLIYEAATRATGIP ARF S GS GS GTEFTL TI S VRQAP GE GLEWVAAIWFD
ASDKYYADAVKGRFTI SR
n AA SLQSEDFAVYYCQQYQNWPLTFGGGTKVEIK
DNSKNTLYLQMNSLRAEDTAVYYCARDLAIFGVVPD
YWGQGTLVTVSS
(SEQ ID NO: 723) (SEQ ID NO: 724)
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGT
GTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGG CCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGC
GCCAGTCAGAGTGTTAACAGACACTTAGCCTGGTAC ATCTGGATTCACCTTCAGTAACTATGGCATGCACTG
CAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATC GGTCCGCCAGGCTCCAGGCGAGGGGCTGGAGTGGG
TACGAAGCAGCCACCAGGGCCACTGGTATCCCAGC TGGCAGCTATATGGTTTGATGCAAGTGATAAATACT
CAGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCAC ATGCAGACGCCGTGAAGGGCCGATTCACCATCTCCA
NA TCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGC GAGACAACTCCAAGAACACGCTGTATCTGCAAATG
AGTTTATTACTGTCAGCAGTATCAGAACTGGCCTCT AACAGCCTGAGAGCCGAGGACACGGCTGTGTATTA
CACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA CTGTGCGAGAGATTTGGCGATTTTTGGAGTGGTCCC
1-3
CGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTC
TAGT
(SEQ ID NO: 725) (SEQ ID NO: 726)
ceo
oo
oo
46
A-2164-WO-PCT
EIVMTQ SP ATL SV SP GERATL SCRASQ SVNRHLAWYQ QVQLVE SGGGVVQPGRSLRL
SCAASGFTFSNYGMHW
QKP GQAPRLLIYEAATRATGIP ARF S GS GS GTEFTL TI S VRQAP GE GLEWVAAIWFD
ASDKYYADAVKGRFTI SR
AA SLQSEDFAVYYCQQYQNWPLTFGGGTKVEIK
DNSKNTLYLQMNSLRAEDTAVYYCARDLAIFGVVPD 0
YWGQGTLVTVSS
n.)
o
(SEQ ID NO: 727) (SEQ ID NO: 728)
oe
i-J
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGT
c,.)
--.1
GTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGG CCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGC
o
--.1
GCCAGTCAGAGTGTTCATAGACACTTAGCCTGGTAC ATCTGGATTCACCTTCAGTAACTATGGCATGCACTG
CAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATC GGTCCGCCAGGCTCCAGGCGAGGGGCTGGAGTGGG
TACGAAGCAGCCACCAGGGCCACTGGTATCCCAGC TGGCAGCTATATGGTTTGATGCAAGTGATAAATACT
CAGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCAC ATGCAGACGCCGTGAAGGGCCGATTCACCATCTCCA
NA
TCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGC GAGACAACTCCAAGAACACGCTGTATCTGCAAATG
AGTTTATTACTGTCAGCAGTATCAGAACTGGCCTCT AACAGCCTGAGAGCCGAGGACACGGCTGTGTATTA
CACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA CTGTGCGAGAGATTTGGCGATTTTTGGAGTGGTCCC
CGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTC
TAGT
p
(SEQ ID NO: 729) (SEQ ID NO: 730)
.
L.
EIVMTQ SP ATL SV SP GERATL SCRASQ SVHRHLAWYQ QVQLVE SGGGVVQPGRSLRL
SCAASGFTFSNYGMHW "
,
re) QKP GQAPRLLIYEAATRATGIP ARF S GS GS GTEFTL TI S VRQAP GE GLEWVAAIWFD
ASDKYYADAVKGRFTI SR .
N,
'el o AA SLQSEDFAVYYCQQYQNWPLTFGGGTKVEIK
DNSKNTLYLQMNSLRAEDTAVYYCARDLAIFGVVPD
PI YWGQGTLVTVSS
(SEQ ID NO: 731) (SEQ ID NO: 732)
,
L.
,
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGT
GTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGG CCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGC
GCCAGTCAGAGTGTTGAAAGACACTTAGCCTGGTAC ATCTGGATTCACCTTCAGTAACTATGGCATGCACTG
CAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATC GGTCCGCCAGGCTCCAGGCGAGGGGCTGGAGTGGG
TACGAAGCAGCCACCAGGGCCACTGGTATCCCAGC TGGCAGCTATATGGTTTGATGCAAGTGATAAATACT
CAGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCAC ATGCAGACGCCGTGAAGGGCCGATTCACCATCTCCA
NA
TCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGC GAGACAACTCCAAGAACACGCTGTATCTGCAAATG
AGTTTATTACTGTCAGCAGTATCAGAACTGGCCTCT AACAGCCTGAGAGCCGAGGACACGGCTGTGTATTA
00
n
c, CACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
CTGTGCGAGAGATTTGGCGATTTTTGGAGTGGTCCC 1-3
o
fl
CGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTC
cp
o n.)
PI TAGT
(SEQ ID NO: 733) (SEQ ID NO: 734)
o
oe
'a
oe
cA
oe
47
A-2164-WO-PCT
EIVMTQ SP ATL SV SPGERATL SCRASQ SVERHLAWYQ QVQLVE SGGGVVQPGRSLRL
SCAASGFTFSNYGMHW
QKP GQAPRLLIYEAATRATGIP ARF S GS GS GTEFTL TI S VRQAP GE GLEWVAAIWFD
ASDKYYADAVKGRFTI SR
AA SLQSEDFAVYYCQQYQNWPLTFGGGTKVEIK
DNSKNTLYLQMNSLRAEDTAVYYCARDLAIFGVVPD 0
YWGQGTLVTVSS
n.)
o
(SEQ ID NO: 735) (SEQ ID NO: 736)
oe
i-J
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGT
c,.)
--.1
GTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGG CCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGC
o
--.1
GCCAGTCAGAGTGTTTTCAGACACTTAGCCTGGTAC ATCTGGATTCACCTTCAGTAACTATGGCATGCACTG
CAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATC GGTCCGCCAGGCTCCAGGCGAGGGGCTGGAGTGGG
TACGAAGCAGCCACCAGGGCCACTGGTATCCCAGC TGGCAGCTATATGGTTTGATGCAAGTGATAAATACT
CAGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCAC ATGCAGACGCCGTGAAGGGCCGATTCACCATCTCCA
NA
TCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGC GAGACAACTCCAAGAACACGCTGTATCTGCAAATG
AGTTTATTACTGTCAGCAGTATCAGAACTGGCCTCT AACAGCCTGAGAGCCGAGGACACGGCTGTGTATTA
CACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA CTGTGCGAGAGATTTGGCGATTTTTGGAGTGGTCCC
CGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTC
TAGT
p
(SEQ ID NO: 737) (SEQ ID NO: 738)
.
L.
EIVMTQ SP ATL SVSP GERATL SCRASQ SVFRHLAWYQ QVQLVE SGGGVVQPGRSLRL
SCAASGFTFSNYGMHW "
,
QKP GQAPRLLIYEAATRATGIP ARF S GS GS GTEFTL TI S VRQAP GE GLEWVAAIWFD
ASDKYYADAVKGRFTI SR .
N,
'1 o AA SLQSEDFAVYYCQQYQNWPLTFGGGTKVEIK
DNSKNTLYLQMNSLRAEDTAVYYCARDLAIFGVVPD
PI YWGQGTLVTVSS
(SEQ ID NO: 739) (SEQ ID NO: 740)
,
L.
,
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGT
GTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGG CCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGC
GCCAGTCAGAGTGTTAACAGACACTTAGCCTGGTAC ATCTGGATTCACCTTCAGTAACTATGGCATGCACTG
CAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATC GGTCCGCCAGGCTCCAGGCGAGGGGCTGGAGTGGG
TACGAAGCAGCCACCAGGGCCACTGGTATCCCAGC TGGCAGCTATATGGTTTGATGCAAGTGATAAATACT
CAGGGTCAGTGGCAGTGGGTCTGGGACAGAGTTCA ATGCAGACGCCGTGAAGGGCCGATTCACCATCTCCA
NA
CTCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTG GAGACAACTCCAAGAACACGCTGTATCTGCAAATG
CAGTTTATTACTGTCAGCAGTATCAGAACTGGCCTC AACAGCCTGAGAGCCGAGGACACGGCTGTGTATTA
00
n
.7r TCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
CTGTGCGAGAGATTTGGCGATTTTTGGAGTGGTCCC 1-3
o
`z.
CGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTC
cp
o n.)
PI TAGT
(SEQ ID NO: 741) (SEQ ID NO: 742)
o
oe
'a
oe
cA
oe
48
A-2164-WO-PCT
EIVMTQ SP ATL SV SP GERATL SCRASQ SVNRHLAWYQ QVQLVE SGGGVVQPGRSLRL
SCAASGFTFSNYGMHW
QKP GQAPRLLIYEAATRATGIP ARVS GS GS GTEFTL TI S VRQAP GE GLEWVAAIWFD
ASDKYYADAVKGRFTI SR
AA SLQSEDFAVYYCQQYQNWPLTFGGGTKVEIK
DNSKNTLYLQMNSLRAEDTAVYYCARDLAIFGVVPD 0
YWGQGTLVTVSS
n.)
o
(SEQ ID NO: 743) (SEQ ID NO: 744)
oe
i-J
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGT
c,.)
--.1
GTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGG CCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGC
o
--.1
GCCAGTCAGAGTGTTGAAAGACACTTAGCCTGGTAC ATCTGGATTCACCTTCAGTAACTATGGCATGCACTG
CAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATC GGTCCGCCAGGCTCCAGGCGAGGGGCTGGAGTGGG
TACGAAGCAGCCACCAGGGCCACTGGTATCCCAGC TGGCAGCTATATGGTTTGATGCAAGTGATAAATACT
CAGGGTCAGTGGCAGTGGGTCTGGGACAGAGTTCA ATGCAGACGCCGTGAAGGGCCGATTCACCATCTCCA
NA
CTCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTG GAGACAACTCCAAGAACACGCTGTATCTGCAAATG
CAGTTTATTACTGTCAGCAGTATCAGAACTGGCCTC AACAGCCTGAGAGCCGAGGACACGGCTGTGTATTA
TCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA CTGTGCGAGAGATTTGGCGATTTTTGGAGTGGTCCC
CGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTC
TAGT
p
(SEQ ID NO: 745) (SEQ ID NO: 746)
.
L.
EIVMTQ SP ATL SV SPGERATL SCRASQ SVERHLAWYQ QVQLVE SGGGVVQPGRSLRL
SCAASGFTFSNYGMHW "
,
o, QKP GQAPRLLIYEAATRATGIP ARVS GS GS GTEFTL TI S VRQAP GE GLEWVAAIWFD
ASDKYYADAVKGRFTI SR .
o N,
AA SLQSEDFAVYYCQQYQNWPLTFGGGTKVEIK
DNSKNTLYLQMNSLRAEDTAVYYCARDLAIFGVVPD
PI YWGQGTLVTVSS
(SEQ ID NO: 747) (SEQ ID NO: 748)
,
L.
,
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGT
GTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGG CCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGC
GCCAGTCAGAGTGTTGATAGACACTTAGCCTGGTAC ATCTGGATTCACCTTCAGTAACTATGGCATGCACTG
CAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATC GGTCCGCCAGGCTCCAGGCGAGGGGCTGGAGTGGG
TACGAAGCAGCCACCAGGGCCACTGGTATCCCAGC TGGCAGCTATATGGTTTGATGCAAGTGATAAATACT
CAGGGTCAGTGGCAGTGGGTCTGGGACAGAGTTCA ATGCAGACGCCGTGAAGGGCCGATTCACCATCTCCA
NA
CTCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTG GAGACAACTCCAAGAACACGCTGTATCTGCAAATG
CAGTTTATTACTGTCAGCAGTATCAGAACTGGCCTC AACAGCCTGAGAGCCGAGGACACGGCTGTGTATTA
00
n
re) TCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
CTGTGCGAGAGATTTGGCGATTTTTGGAGTGGTCCC 1-3
o
`z.
CGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTC
cp
o n.)
PI TAGT
(SEQ ID NO: 749) (SEQ ID NO: 750)
o
oe
'a
oe
cA
oe
49
A-2164-WO-PCT
EIVMTQ SP ATL SV SP GERATL SCRASQ SVDRHLAWYQ QVQLVE SGGGVVQPGRSLRL
SCAASGFTFSNYGMHW
QKP GQAPRLLIYEAATRATGIP ARVS GS GS GTEFTL TI S VRQAP GE GLEWVAAIWFD
ASDKYYADAVKGRFTI SR
AA SLQSEDFAVYYCQQYQNWPLTFGGGTKVEIK
DNSKNTLYLQMNSLRAEDTAVYYCARDLAIFGVVPD 0
YWGQGTLVTVSS
n.)
o
(SEQ ID NO: 751) (SEQ ID NO: 752)
oe
i-J
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGT
c,.)
--.1
GTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGG CCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGC
o
--.1
GCCAGTCAGAGTGTTCTGAGTCACTTAGCCTGGTAC ATCTGGATTCACCTTCAGTAACTATGGCATGCACTG
CAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATC GGTCCGCCAGGCTCCAGGCGAGGGGCTGGAGTGGG
TACGAAGCAGCCACCAGGGCCACTGGTATCCCAGC TGGCAGCTATATGGTTTGATGCAAGTGATAAATACT
CAGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCAC ATGCAGACGCCGTGAAGGGCCGATTCACCATCTCCA
NA
TCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGC GAGACAACTCCAAGAACACGCTGTATCTGCAAATG
AGTTTATTACTGTCAGCAGTATAACAACTGGCCTCT AACAGCCTGAGAGCCGAGGACACGGCTGTGTATTA
CACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA CTGTGCGAGAGATTTGGCGATTTTTGGAGTGGTCCC
CGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTC
TAGT
p
(SEQ ID NO: 753) (SEQ ID NO: 754)
.
L.
EIVMTQ SP ATL SV SP GERATL SCRASQ SVL SHL AWYQ QVQLVE SGGGVVQPGRSLRL
SCAASGFTFSNYGMHW "
,
co QKP GQAPRLLIYEAATRATGIP ARF S GS GS GTEFTL TI S VRQAP GE GLEWVAAIWFD
ASDKYYADAVKGRFTI SR .
N,
n o AA SLQSEDFAVYYCQQYNNWPLTFGGGTKVEIK
DNSKNTLYLQMNSLRAEDTAVYYCARDLAIFGVVPD
PI YWGQGTLVTVSS
(SEQ ID NO: 755) (SEQ ID NO: 756)
,
L.
,
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGT
GTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGG CCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGC
GCCAGTCAGAGTGTTCTGAGTCACTTAGCCTGGTAC ATCTGGATTCACCTTCAGTAACTATGGCATGCACTG
CAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATC GGTCCGCCAGGCTCCAGGCGAGGGGCTGGAGTGGG
TACGAAGCAGCCACCAGGGCCACTGGTATCCCAGC TGGCAGCTATATGGTTTGATGCAAGTGATAAATACT
CAGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCAC ATGCAGACGCCGTGAAGGGCCGATTCACCATCTCCA
NA
TCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGC GAGACAACTCCAAGAACACGCTGTATCTGCAAATG
AGTTTATTACTGTCAGCAGTATCAGAACTGGCCTCT AACAGCCTGAGAGCCGAGGACACGGCTGTGTATTA
00
n
.7r CACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
CTGTGCGAGAGATTTGGCGATTTTTGGAGTGGTCCC 1-3
n
CGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTC
cp
o n.)
PI TAGT
(SEQ ID NO: 757) (SEQ ID NO: 758)
o
oe
'a
oe
cA
oe
A-2164-WO-PCT
EIVMTQ SP ATL SV SP GERATL SCRASQ SVL SHL AWYQ QVQLVE SGGGVVQPGRSLRL
SCAASGFTFSNYGMHW
QKP GQAPRLLIYEAATRATGIP ARF S GS GS GTEFTL TI S VRQAP GE GLEWVAAIWFD
ASDKYYADAVKGRFTI SR
AA SLQSEDFAVYYCQQYQNWPLTFGGGTKVEIK
DNSKNTLYLQMNSLRAEDTAVYYCARDLAIFGVVPD 0
YWGQGTLVTVSS
n.)
o
(SEQ ID NO: 759) (SEQ ID NO: 760)
oe
i-J
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGT
c,.)
--.1
GTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGG CCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGC
o
--.1
GCCAGTCAGAGTGTTATGAGTCACTTAGCCTGGTAC ATCTGGATTCACCTTCAGTAACTATGGCATGCACTG
CAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATC GGTCCGCCAGGCTCCAGGCGAGGGGCTGGAGTGGG
TACGAAGCAGCCACCAGGGCCACTGGTATCCCAGC TGGCAGCTATATGGTTTGATGCAAGTGATAAATACT
CAGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCAC ATGCAGACGCCGTGAAGGGCCGATTCACCATCTCCA
NA
TCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGC GAGACAACTCCAAGAACACGCTGTATCTGCAAATG
AGTTTATTACTGTCAGCAGTATCAGAACTGGCCTCT AACAGCCTGAGAGCCGAGGACACGGCTGTGTATTA
CACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA CTGTGCGAGAGATTTGGCGATTTTTGGAGTGGTCCC
CGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTC
TAGT
p
(SEQ ID NO: 761) (SEQ ID NO: 762)
.
L.
EIVMTQ SP ATL SV SP GERATL SCRASQ SVM SHL AWYQ QVQLVE SGGGVVQPGRSLRL
SCAASGFTFSNYGMHW "
,
QKP GQAPRLLIYEAATRATGIP ARF S GS GS GTEFTL TI S VRQAP GE GLEWVAAIWFD
ASDKYYADAVKGRFTI SR .
N,
n o AA SLQSEDFAVYYCQQYQNWPLTFGGGTKVEIK
DNSKNTLYLQMNSLRAEDTAVYYCARDLAIFGVVPD
PI YWGQGTLVTVSS
(SEQ ID NO: 763) (SEQ ID NO: 764)
,
L.
,
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGT
GTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGG CCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGC
GCCAGTCAGAGTGTTCTGACGCACTTAGCCTGGTAC ATCTGGATTCACCTTCAGTAACTATGGCATGCACTG
CAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATC GGTCCGCCAGGCTCCAGGCGAGGGGCTGGAGTGGG
TACGAAGCAGCCACCAGGGCCACTGGTATCCCAGC TGGCAGCTATATGGTTTGATGCAAGTGATAAATACT
CAGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCAC ATGCAGACGCCGTGAAGGGCCGATTCACCATCTCCA
NA
TCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGC GAGACAACTCCAAGAACACGCTGTATCTGCAAATG
AGTTTATTACTGTCAGCAGTATCAGAACTGGCCTCT AACAGCCTGAGAGCCGAGGACACGGCTGTGTATTA
00
n
in CACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
CTGTGCGAGAGATTTGGCGATTTTTGGAGTGGTCCC 1-3
,-
n
CGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTC
cp
o n.)
PI TAGT
(SEQ ID NO: 765) (SEQ ID NO: 766)
o
oe
'a
oe
cA
oe
51
A-2164-WO-PCT
EIVMTQ SP ATL SV SP GERATL SCRASQ SVLTHLAWYQ QVQLVE SGGGVVQPGRSLRL
SCAASGFTFSNYGMHW
QKP GQAPRLLIYEAATRATGIP ARF S GS GS GTEFTL TI S VRQAP GE GLEWVAAIWFD
ASDKYYADAVKGRFTI SR
AA SLQSEDFAVYYCQQYQNWPLTFGGGTKVEIK
DNSKNTLYLQMNSLRAEDTAVYYCARDLAIFGVVPD 0
YWGQGTLVTVSS
n.)
o
(SEQ ID NO: 767) (SEQ ID NO: 768)
oe
i-J
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGT
c,.)
--.1
GTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGG CCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGC
o
--.1
GCCAGTCAGAGTGTTGATCTGCACTTAGCCTGGTAC ATCTGGATTCACCTTCAGTAACTATGGCATGCACTG
CAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATC GGTCCGCCAGGCTCCAGGCGAGGGGCTGGAGTGGG
TACGAAGCAGCCACCAGGGCCACTGGTATCCCAGC TGGCAGCTATATGGTTTGATGCAAGTGATAAATACT
CAGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCAC ATGCAGACGCCGTGAAGGGCCGATTCACCATCTCCA
NA
TCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGC GAGACAACTCCAAGAACACGCTGTATCTGCAAATG
AGTTTATTACTGTCAGCAGTATCAGAACTGGCCTCT AACAGCCTGAGAGCCGAGGACACGGCTGTGTATTA
CACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA CTGTGCGAGAGATTTGGCGATTTTTGGAGTGGTCCC
CGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTC
TAGT
p
(SEQ ID NO: 769) (SEQ ID NO: 770)
.
L.
EIVMTQ SP ATL SVSPGERATL SCRASQSVDLHLAWYQ QVQLVE SGGGVVQPGRSLRL
SCAASGFTFSNYGMHW "
,
,- QKP GQAPRLLIYEAATRATGIP ARF S GS GS GTEFTL TI S VRQAP GE GLEWVAAIWFD
ASDKYYADAVKGRFTI SR .
f el o AA SLQSEDFAVYYCQQYQNWPLTFGGGTKVEIK
DNSKNTLYLQMNSLRAEDTAVYYCARDLAIFGVVPD
PI YWGQGTLVTVSS
(SEQ ID NO: 771) (SEQ ID NO: 772)
,
L.
,
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGT
GTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGG CCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGC
GCCAGTCAGAGTGTTAGCGAACACTTAGCCTGGTAC ATCTGGATTCACCTTCAGTAACTATGGCATGCACTG
CAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATC GGTCCGCCAGGCTCCAGGCGAGGGGCTGGAGTGGG
TACGAAGCAGCCACCAGGGCCACTGGTATCCCAGC TGGCAGCTATATGGTTTGATGCAAGTGATAAATACT
CAGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCAC ATGCAGACGCCGTGAAGGGCCGATTCACCATCTCCA
NA
TCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGC GAGACAACTCCAAGAACACGCTGTATCTGCAAATG
AGTTTATTACTGTCAGCAGTATCAGAACTGGCCTCT AACAGCCTGAGAGCCGAGGACACGGCTGTGTATTA
00
n
o
CACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
CTGTGCGAGAGATCTGGCGATTTTTGGAGTGATTCC 1-3
fl
CGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTC
cp
o n.)
PI TAGT
(SEQ ID NO: 773) (SEQ ID NO: 774)
o
oe
'a
oe
cA
oe
52
A-2164-WO-PCT
EIVMTQ SP ATL SV SP GERATL SCRASQ SVSEHL AWYQ QVQLVE SGGGVVQPGRSLRL
SCAASGFTFSNYGMHW
QKP GQAPRLLIYEAATRATGIP ARF S GS GS GTEFTL TI S VRQAP GE GLEWVAAIWFD
ASDKYYADAVKGRFTI SR
AA SLQSEDFAVYYCQQYQNWPLTFGGGTKVEIK
DNSKNTLYLQMNSLRAEDTAVYYCARDLAIFGVIPDY 0
WGQGTLVTVSS
n.)
o
(SEQ ID NO: 775) (SEQ ID NO: 776)
oe
i-J
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGT
c,.)
--.1
GTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGG CCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGC
o
--.1
GCCAGTCAGAGTGTTAGCGAACACTTAGCCTGGTAC ATCTGGATTCACCTTCAGTAACTATGGCATGCACTG
CAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATC GGTCCGCCAGGCTCCAGGCGAGGGGCTGGAGTGGG
TACGAAGCAGCCACCAGGGCCACTGGTATCCCAGC TGGCAGCTATATGGTTTGATGCAAGTGATAAATACT
CAGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCAC ATGCAGACGCCGTGAAGGGCCGATTCACCATCTCCA
NA
TCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGC GAGACAACTCCAAGAACACGCTGTATCTGCAAATG
AGTTTATTACTGTCAGCAGTATCAGAACTGGCCTCT AACAGCCTGAGAGCCGAGGACACGGCTGTGTATTA
CACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA CTGTGCGAGAGATTTGGCGATTTTTGGAGTGGTCCC
CGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTC
TAGT
p
(SEQ ID NO: 777) (SEQ ID NO: 778)
.
L.
EIVMTQ SP ATL SV SP GERATL SCRASQ SVSEHL AWYQ QVQLVE SGGGVVQPGRSLRL
SCAASGFTFSNYGMHW "
,
co QKP GQAPRLLIYEAATRATGIP ARF S GS GS GTEFTL TI S VRQAP GE GLEWVAAIWFD
ASDKYYADAVKGRFTI SR .
N,
n o AA SLQSEDFAVYYCQQYQNWPLTFGGGTKVEIK
DNSKNTLYLQMNSLRAEDTAVYYCARDLAIFGVVPD
PI YWGQGTLVTVSS
(SEQ ID NO: 779) (SEQ ID NO: 780)
,
L.
,
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGT
GTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGG CCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGC
GCCAGTCAGAGTGTTAGCCGGCACTTAGCCTGGTAC ATCTGGATTCACCTTCAGTAACTATGGCATGCACTG
CAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATC GGTCCGCCAGGCTCCAGGCGAGGGGCTGGAGTGGG
TACGAAGCAGCCACCAGGGCCACTGGTATCCCAGC TGGCAGCTATATGGTTTGATGCAAGTGATAAATACT
CAGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCAC ATGCAGACGCCGTGAAGGGCCGATTCACCATCTCCA
NA
TCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGC GAGACAACTCCAAGAACACGCTGTATCTGCAAATG
AGTTTATTACTGTCAGCAGTATCAGCACTGGCCTCT AACAGCCTGAGAGCCGAGGACACGGCTGTGTATTA
00
n
f 9) CACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
CTGTGCGAGAGATTTGGCGATTTTTGGAGTGGTCCC 1-3
f 9)
n
CGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTC
cp
o n.)
PI TAGT
(SEQ ID NO: 781) (SEQ ID NO: 782)
o
oe
'a
oe
cA
oe
53
A-2164-WO-PCT
EIVMTQ SP ATL SVSP GERATL SCRASQ SVSRHLAWYQ QVQLVE SGGGVVQPGRSLRL
SCAASGFTFSNYGMHW
QKP GQAPRLLIYEAATRATGIP ARF S GS GS GTEFTL TI S VRQAP GE GLEWVAAIWFD
ASDKYYADAVKGRFTI SR
AA SLQSEDFAVYYCQQYQHWPLTFGGGTKVEIK
DNSKNTLYLQMNSLRAEDTAVYYCARDLAIFGVVPD 0
YWGQGTLVTVSS
n.)
o
(SEQ ID NO: 783) (SEQ ID NO: 784)
oe
i-J
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGT
c,.)
--.1
GTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGG CCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGC
o
--.1
GCCAGTCAGAGTGTTTTCAGCCACTTAGCCTGGTAC ATCTGGATTCACCTTCCAGAACTATGGCATGCACTG
CAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATC GGTCCGCCAGGCTCCAGGCGAGGGGCTGGAGTGGG
TACGAAGCAGCCACCAGGGCCACTGGTATCCCAGC TGGCAGCTATATGGTTTGATGCGTCTGACAAATACT
CAGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCAC ATGCAGACGCCGTGAAGGGCCGATTCACCATCTCCA
NA
TCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGC GAGACAACTCCAAGAACACGCTGTATCTGCAAATG
AGTTTATTACTGTCAGCAGTATCAGAACTGGCCTCT AACAGCCTGAGAGCCGAGGACACGGCTGTGTATTA
CACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA CTGTGCGAGAGATCTTGCGATTTTTGGAGTGGTCCC
CGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTC
TAGT
p
(SEQ ID NO: 785) (SEQ ID NO: 786)
.
L.
EIVMTQ SP ATL SVSPGERATL SCRASQSVFSHLAWYQQ QVQLVESGGGVVQPGRSLRL
SCAASGFTFQNYGMHW "
,
,- KPGQAPRLLIYEAATRATGIPARFSGSGSGTEFTLTISSL
VRQAPGEGLEWVAAIWFDASDKYYADAVKGRFTISR .
o N,
'1 o AA QSEDFAVYYCQQYQNWPLTFGGGTKVEIK
DNSKNTLYLQMNSLRAEDTAVYYCARDLAIFGVVPD
PI YWGQGTLVTVSS
(SEQ ID NO: 787) (SEQ ID NO: 788)
,
L.
,
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGT
GTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGG CCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGC
GCCAGTCAGAGTGTTTTCAGCCACTTAGCCTGGTAC ATCTGGATTCACCTTCCAGAACTATGGCATGCACTG
CAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATC GGTCCGCCAGGCTCCAGGCGAGGGGCTGGAGTGGG
TACGAAGCAGCCACCAGGGCCACTGGTATCCCAGC TGGCAGCTATATGGTTTGATGCGTCTGACAAATACT
CAGGGTCAGTGGCAGTGGGTCTGGGACAGAGTTCA ATGCAGACGCCGTGAAGGGCCGATTCACCATCTCCA
NA
CTCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTG GAGACAACTCCAAGAACACGCTGTATCTGCAAATG
CAGTTTATTACTGTCAGCAGTATCAGAACTGGCCTC AACAGCCTGAGAGCCGAGGACACGGCTGTGTATTA
00
n
,- TCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
CTGTGCGAGAGATCTTGCGATTTTTGGAGTGGTCCC 1-3
o
`z.
CGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTC
cp
o n.)
PI TAGT
(SEQ ID NO: 789) (SEQ ID NO: 790)
o
oe
'a
oe
cA
oe
54
A-2164-W0- P CT
EIVMTQ SP ATL SVSPGERATLSCRASQSVFSHLAWYQQ QVQLVESGGGVVQPGRSLRL
SCAASGFTFQNYGMHW
KP GQAPRLLIYEAATRAT GIP ARVS GS GS GTEFTL TI S S VRQAP GE GLEWVAAIWFD
ASDKYYADAVKGRFTI SR
AA LQSEDFAVYYCQQYQNWPLTFGGGTKVEIK
DNSKNTLYLQMNSLRAEDTAVYYCARDLAIFGVVPD 0
YWGQGTLVTVSS
n.)
o
(SEQ ID NO: 791) (SEQ ID NO: 792)
oe
i-J
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGT
c,.)
--.1
GTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGG CCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGC
o
--.1
GCCAGTCAGAGTGTTCTGAGTCACTTAGCCTGGTAC ATCTGGATTCACCTTCCAGAACTATGGCATGCACTG
CAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATC GGTCCGCCAGGCTCCAGGCGAGGGGCTGGAGTGGG
TACGAAGCAGCCACCAGGGCCACTGGTATCCCAGC TGGCAGCTATATGGTTTGATGCGTCTGACAAATACT
CAGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCAC ATGCAGACGCCGTGAAGGGCCGATTCACCATCTCCA
NA
TCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGC GAGACAACTCCAAGAACACGCTGTATCTGCAAATG
AGTTTATTACTGTCAGCAGTATCAGCAGTGGCCTCT AACAGCCTGAGAGCCGAGGACACGGCTGTGTATTA
CACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA CTGTGCGAGAGATCTTGCGATTTTTGGAGTGGTCCC
CGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTC
TAGT
p
(SEQ ID NO: 793) (SEQ ID NO: 793)
.
L.
EIVMTQ SP ATL SV SP GERATL SCRASQ SVL SHL AWYQ QVQLVESGGGVVQPGRSLRL
SCAASGFTFQNYGMHW "
,
QKP GQAPRLLIYEAATRATGIP ARF S GS GS GTEFTL TI S VRQAP GE GLEWVAAIWFD
ASDKYYADAVKGRFTI SR .
N,
n o AA SLQSEDFAVYYCQQYQQWPLTFGGGTKVEIK
DNSKNTLYLQMNSLRAEDTAVYYCARDLAIFGVVPD
PI YWGQGTLVTVSS
(SEQ ID NO: 75) (SEQ ID NO: 796)
,
L.
,
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGT
GTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGG CCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGC
GCCAGTCAGAGTGTTTTCAGCCACTTAGCCTGGTAC ATCTGGATTCACCTTCAGTAACTATGGCATGCACTG
CAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATC GGTCCGCCAGGCTCCAGGCGAGGGGCTGGAGTGGG
TACGAAGCAGCCACCAGGGCCACTGGTATCCCAGC TGGCAGCTATATGGTTTGATGCAAGTGATAAATACT
CAGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCAC ATGCAGACGCCGTGAAGGGCCGATTCACCATCTCCA
NA
TCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGC GAGACAACTCCAAGAACACGCTGTATCTGCAAATG
AGTTTATTACTGTCAGCAGTATCAGCAGTGGCCTCT AACAGCCTGAGAGCCGAGGACACGGCTGTGTATTA
00
n
co CACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
CTGTGCGAGAGATTTGGCGATTTTTGGAGTGGTCCC 1-3
o
n
CGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTC
cp
o n.)
PI TAGT
(SEQ ID NO: 797) (SEQ ID NO: 798)
o
oe
'a
oe
cA
oe
A-2164-W0- P CT
EIVMTQ SP ATL SVSPGERATLSCRASQSVFSHLAWYQQ QVQLVE SGGGVVQPGRSLRL
SCAASGFTFSNYGMHW
KPGQAPRLLIYEAATRATGIPARFSGSGSGTEFTLTISSL VRQAPGEGLEWVAAIWFDASDKYYADAVKGRFTISR
AA QSEDFAVYYCQQYQQWPLTFGGGTKVEIK
DNSKNTLYLQMNSLRAEDTAVYYCARDLAIFGVVPD 0
YWGQGTLVTVSS
n.)
o
(SEQ ID NO: 799) (SEQ ID NO: 800)
oe
i-J
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGT
c,.)
--.1
GTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGG CCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGC
o
--.1
GCCAGTCAGAGTGTTTTCAGCCACTTAGCCTGGTAC ATCTGGATTCACCTTCAGTAACTATGGCATGCACTG
CAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATC GGTCCGCCAGGCTCCAGGCGAGGGGCTGGAGTGGG
TACGAAGCAGCCACCAGGGCCACTGGTATCCCAGC TGGCAGCTATATGGTTTGATGCAAGTGATAAATACT
CAGGGTCAGTGGCAGTGGGTCTGGGACAGAGTTCA ATGCAGACGCCGTGAAGGGCCGATTCACCATCTCCA
NA
CTCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTG GAGACAACTCCAAGAACACGCTGTATCTGCAAATG
CAGTTTATTACTGTCAGCAGTATCAGCAGTGGCCTC AACAGCCTGAGAGCCGAGGACACGGCTGTGTATTA
TCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA CTGTGCGAGAGATTTGGCGATTTTTGGAGTGGTCCC
CGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTC
TAGT
p
(SEQ ID NO: 801) (SEQ ID NO: 802)
.
L.
EIVMTQ SP ATL SVSPGERATL SCRASQSVFSHLAWYQQ QVQLVE SGGGVVQPGRSLRL
SCAASGFTFSNYGMHW "
,
co KP GQAPRLLIYEAATRAT GIP ARVS GS GS GTEFTL TI S S VRQAP GE
GLEWVAAIWFD ASDKYYADAVKGRFTI SR .
o N,
AA LQSEDFAVYYCQQYQQWPLTFGGGTKVEIK
DNSKNTLYLQMNSLRAEDTAVYYCARDLAIFGVVPD
PI YWGQGTLVTVSS
(SEQ ID NO: 803) (SEQ ID NO: 804)
,
L.
,
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGT
GTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGG CCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGC
GCCAGTCAGAGTGTTCAGAGCCACTTAGCCTGGTAC ATCTGGATTCACCTTCAGTAACTATGGCATGCACTG
CAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATC GGTCCGCCAGGCTCCAGGCGAGGGGCTGGAGTGGG
TACGAAGCAGCCACCAGGGCCACTGGTATCCCAGC TGGCAGCTATATGGTTTGATGCAAGTGATAAATACT
CAGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCAC ATGCAGACGCCGTGAAGGGCCGATTCACCATCTCCA
NA
TCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGC GAGACAACTCCAAGAACACGCTGTATCTGCAAATG
AGTTTATTACTGTCAGCAGTATCAGAACTGGCCTCT AACAGCCTGAGAGCCGAGGACACGGCTGTGTATTA
00
n
CACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA CTGTGCGAGAGATATTGCGATTTTTGGAGTGGTCCC
1-3
f e)
f el
CGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTC
cp
o n.)
PI TAGT
(SEQ ID NO: 805) (SEQ ID NO: 806)
o
oe
'a
oe
cA
oe
56
A-2164-W0- P CT
EIVMTQ SP ATL SVSPGERATL SCRASQSVQSHLAWYQ QVQLVE SGGGVVQPGRSLRL
SCAASGFTFSNYGMHW
QKP GQAPRLLIYEAATRATGIP ARF S GS GS GTEFTL TI S VRQAP GE GLEWVAAIWFD
ASDKYYADAVKGRFTI SR
AA SLQSEDFAVYYCQQYQNWPLTFGGGTKVEIK
DNSKNTLYLQMNSLRAEDTAVYYCARDIAIFGVVPDY 0
WGQGTLVTVSS
n.)
o
(SEQ ID NO: 807) (SEQ ID NO: 808)
oe
i-J
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGT
c,.)
--.1
GTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGG CCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGC
o
--.1
GCCAGTCAGAGTGTTAGTAGCCACTTAGCCTGGTAC ATCTGGATTCACCTTCAGTAACTATGGCATGCACTG
CAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATC GGTCCGCCAGGCTCCAGGCGAGGGGCTGGAGTGGG
TACGAAGCAGCCACCAGGGCCACTGGTATCCCAGC TGGCAGCTATATGGTTTGATGCAAGTGATAAATACT
CAGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCAC ATGCAGACGCCGTGAAGGGCCGATTCACCATCTCCA
NA
TCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGC GAGACAACTCCAAGAACACGCTGTATCTGCAAATG
AGTTTATTACTGTCAGCAGTATCAGCAGTGGCCTCT AACAGCCTGAGAGCCGAGGACACGGCTGTGTATTA
CACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA CTGTGCGAGAGATATTGCGATTTTTGGAGTGGTCCC
CGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTC
TAGT
p
(SEQ ID NO: 809) (SEQ ID NO: 810)
.
L.
EIVMTQ SP ATL SVSPGERATL SCRASQSVS SHLAWYQQ QVQLVE SGGGVVQPGRSLRL
SCAASGFTFSNYGMHW "
,
.7r KPGQAPRLLIYEAATRATGIPARFSGSGSGTEFTLTISSL
VRQAPGEGLEWVAAIWFDASDKYYADAVKGRFTISR .
.7r
N,
n o AA QSEDFAVYYCQQYQQWPLTFGGGTKVEIK
DNSKNTLYLQMNSLRAEDTAVYYCARDIAIFGVVPDY
PI WGQGTLVTVSS
(SEQ ID NO: 811) (SEQ ID NO: 812)
,
L.
,
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGT
GTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGG CCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGC
GCCAGTCAGAGTGTTTTCACGCACTTAGCCTGGTAC ATCTGGATTCACCTTCAGTAACTATGGCATGCACTG
CAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATC GGTCCGCCAGGCTCCAGGCGAGGGGCTGGAGTGGG
TACGAAGCAGCCACCAGGGCCACTGGTATCCCAGC TGGCAGCTATATGGTTTGATGCAAGTGATAAATACT
CAGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCAC ATGCAGACGCCGTGAAGGGCCGATTCACCATCTCCA
NA
TCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGC GAGACAACTCCAAGAACACGCTGTATCTGCAAATG
AGTTTATTACTGTCAGCAGTATAACAACTGGCCTCT AACAGCCTGAGAGCCGAGGACACGGCTGTGTATTA
00
n
o
CACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
CTGTGCGAGAGATTTGGCGATTTTTGGAGTGGTCCC 1-3
,-
'91
CGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTC
cp
o n.)
PI TAGT
(SEQ ID NO: 813) (SEQ ID NO: 814)
o
oe
'a
oe
cA
oe
57
A-2164-WO-PCT
EIVMTQ SP ATL SV SP GERATL SCRASQ SVFTHL AWYQ QVQLVE SGGGVVQPGRSLRL
SCAASGFTFSNYGMHW
QKP GQAPRLLIYEAATRATGIP ARF S GS GS GTEFTL TI S VRQAP GE GLEWVAAIWFD
ASDKYYADAVKGRFTI SR
AA SLQSEDFAVYYCQQYNNWPLTFGGGTKVEIK
DNSKNTLYLQMNSLRAEDTAVYYCARDLAIFGVVPD 0
YWGQGTLVTVSS
n.)
o
(SEQ ID NO: 815) (SEQ ID NO: 816)
oe
i-J
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGT
c,.)
--.1
GTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGG CCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGC
o
--.1
GCCAGTCAGAGTGTTTTCACGCACTTAGCCTGGTAC ATCTGGATTCACCTTCAGTAACTATGGCATGCACTG
CAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATC GGTCCGCCAGGCTCCAGGCGAGGGGCTGGAGTGGG
TACGAAGCAGCCACCAGGGCCACTGGTATCCCAGC TGGCAGCTATATGGTTTGATGCAAGTGATAAATACT
CAGGGTCAGTGGCAGTGGGTCTGGGACAGAGTTCA ATGCAGACGCCGTGAAGGGCCGATTCACCATCTCCA
NA
CTCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTG GAGACAACTCCAAGAACACGCTGTATCTGCAAATG
CAGTTTATTACTGTCAGCAGTATAACAACTGGCCTC AACAGCCTGAGAGCCGAGGACACGGCTGTGTATTA
TCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA CTGTGCGAGAGATTTGGCGATTTTTGGAGTGGTCCC
CGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTC
TAGT
p
(SEQ ID NO: 817) (SEQ ID NO: 818)
.
L.
EIVMTQ SP ATL SV SP GERATL SCRASQ SVFTHL AWYQ QVQLVE SGGGVVQPGRSLRL
SCAASGFTFSNYGMHW "
,
o
QKP GQAPRLLIYEAATRATGIP ARVS GS GS
GTEFTL TI S VRQAP GE GLEWVAAIWFD ASDKYYADAVKGRFTI SR .
N,
AA SLQSEDFAVYYCQQYNNWPLTFGGGTKVEIK
DNSKNTLYLQMNSLRAEDTAVYYCARDLAIFGVVPD
PI YWGQGTLVTVSS
(SEQ ID NO: 819) (SEQ ID NO: 820)
,
L.
,
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGT
GTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGG CCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGC
GCCAGTCAGAGTGTTTTTGAACACTTAGCCTGGTAC ATCTGGATTCACCTTCAGTAACTATGGCATGCACTG
CAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATC GGTCCGCCAGGCTCCAGGCGAGGGGCTGGAGTGGG
TACGAAGCAGCCACCAGGGCCACTGGTATCCCAGC TGGCAGCTATATGGTTTGATGCAAGTGATAAATACT
CAGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCAC ATGCAGACGCCGTGAAGGGCCGATTCACCATCTCCA
NA
TCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGC GAGACAACTCCAAGAACACGCTGTATCTGCAAATG
AGTTTATTACTGTCAGCAGTATAACAACTGGCCTCT AACAGCCTGAGAGCCGAGGACACGGCTGTGTATTA
00
n
CACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA CTGTGCGAGAGATTTGGCGATTTTTGGAGTGGTCCC
1-3
,-
n
CGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTC
cp
o n.)
PI TAGT
(SEQ ID NO: 821) (SEQ ID NO: 822)
o
oe
'a
oe
cA
oe
58
A-2164-WO-PCT
EIVMTQ SP ATL SV SP GERATL SCRASQ SVFEHL AWYQ QVQLVE SGGGVVQPGRSLRL
SCAASGFTFSNYGMHW
QKP GQAPRLLIYEAATRATGIP ARF S GS GS GTEFTL TI S VRQAP GE GLEWVAAIWFD
ASDKYYADAVKGRFTI SR
AA SLQSEDFAVYYCQQYNNWPLTFGGGTKVEIK
DNSKNTLYLQMNSLRAEDTAVYYCARDLAIFGVVPD 0
YWGQGTLVTVSS
n.)
o
(SEQ ID NO: 823) (SEQ ID NO: 824)
oe
i-J
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGT
c,.)
--.1
GTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGG CCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGC
o
--.1
GCCAGTCAGAGTGTTGAACAGCACTTAGCCTGGTAC ATCTGGATTCACCTTCAGTAACTATGGCATGCACTG
CAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATC GGTCCGCCAGGCTCCAGGCGAGGGGCTGGAGTGGG
TACGAAGCAGCCACCAGGGCCACTGGTATCCCAGC TGGCAGCTATATGGTTTGATGCAAGTGATAAATACT
CAGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCAC ATGCAGACGCCGTGAAGGGCCGATTCACCATCTCCA
NA
TCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGC GAGACAACTCCAAGAACACGCTGTATCTGCAAATG
AGTTTATTACTGTCAGCAGTATAACAACTGGCCTCT AACAGCCTGAGAGCCGAGGACACGGCTGTGTATTA
CACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA CTGTGCGAGAGATTTGGCGATTTTTGGAGTGGTCCC
CGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTC
TAGT
p
(SEQ ID NO: 825) (SEQ ID NO: 826)
.
L.
EIVMTQ SP ATL SV SPGERATL SCRASQ SVEQHLAWYQ QVQLVE SGGGVVQPGRSLRL
SCAASGFTFSNYGMHW "
,
o, QKP GQAPRLLIYEAATRATGIP ARF S GS GS GTEFTL TI S VRQAP GE GLEWVAAIWFD
ASDKYYADAVKGRFTI SR .
N,
n o AA SLQSEDFAVYYCQQYNNWPLTFGGGTKVEIK
DNSKNTLYLQMNSLRAEDTAVYYCARDLAIFGVVPD
PI YWGQGTLVTVSS
(SEQ ID NO: 827) (SEQ ID NO: 828)
,
L.
,
GAAATAGTGATGACGCAGTCTCCGGCCACCCTGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGT
GTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGG CCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGC
GCCAGTCAGAGTGTTCATAGCCACTTAGCCTGGTAC ATCTGGATTCACCTTCAGTAACTATGGCATGCACTG
CAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATC GGTCCGCCAGGCTCCAGGCGAGGGGCTGGAGTGGG
TACGAAGCAGCCACCAGGGCCACTGGTATCCCAGC TGGCAGCTATATGGTTTGATGCAAGTGATAAATACT
CAGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCAC ATGCAGACGCCGTGAAGGGCCGATTCACCATCTCCA
NA
TCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGC GAGACAACTCCAAGAACACGCTGTATCTGCAAATG
AGTTTATTACTGTCAGCAGTATAACCAGTGGCCTCT AACAGCCTGAGAGCCGAGGACACGGCTGTGTATTA
00
n
N CACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
CTGTGCGAGAGATTTGGCGATTTTTGGAGTGGTCCC 1-3
n
CGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTC
cp
o n.)
PI TAGT
(SEQ ID NO: 829) (SEQ ID NO: 830)
o
oe
'a
oe
cA
oe
59
A-2164-W0- P CT
EIVMTQ SP ATL SVSPGERATL SCRASQSVHSHLAWYQ QVQLVE SGGGVVQPGRSLRL
SCAASGFTFSNYGMHW
QKP GQAPRLLIYEAATRATGIP ARF S GS GS GTEFTL TI S VRQAP GE GLEWVAAIWFD
ASDKYYADAVKGRFTI SR
AA SLQSEDFAVYYCQQYNQWPLTFGGGTKVEIK
DNSKNTLYLQMNSLRAEDTAVYYCARDLAIFGVVPD 0
YWGQGTLVTVSS
n.)
o
(SEQ ID NO: 831) (SEQ ID NO: 832)
oe
i-J
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGT
c,.)
--.1
GTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGG CCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGC
o
--.1
GCCAGTCAGAGTGTTCATCATCACTTAGCCTGGTAC ATCTGGATTCACCTTCAGTAACTATGGCATGCACTG
CAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATC GGTCCGCCAGGCTCCAGGCGAGGGGCTGGAGTGGG
TACGAAGCAGCCACCAGGGCCACTGGTATCCCAGC TGGCAGCTATATGGTTTGATGCAAGTGATAAATACT
CAGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCAC ATGCAGACGCCGTGAAGGGCCGATTCACCATCTCCA
NA
TCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGC GAGACAACTCCAAGAACACGCTGTATCTGCAAATG
AGTTTATTACTGTCAGCAGTATAACCAGTGGCCTCT AACAGCCTGAGAGCCGAGGACACGGCTGTGTATTA
CACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA CTGTGCGAGAGATTTGGCGATTTTTGGAGTGGTCCC
CGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTC
TAGT
p
(SEQ ID NO: 833) (SEQ ID NO: 834)
.
L.
EIVMTQ SP ATL SVSPGERATL SCRASQSVHHHLAWYQ QVQLVE SGGGVVQPGRSLRL
SCAASGFTFSNYGMHW "
,
co QKP GQAPRLLIYEAATRATGIP ARF S GS GS GTEFTL TI S VRQAP GE GLEWVAAIWFD
ASDKYYADAVKGRFTI SR .
f el o AA SLQSEDFAVYYCQQYNQWPLTFGGGTKVEIK
DNSKNTLYLQMNSLRAEDTAVYYCARDLAIFGVVPD
PI YWGQGTLVTVSS
(SEQ ID NO: 835) (SEQ ID NO: 836)
,
L.
,
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGT
GTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGG CCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGC
GCCAGTCAGAGTGTTCATAGCCACTTAGCCTGGTAC ATCTGGATTCACCTTCAGTAACTATGGCATGCACTG
CAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATC GGTCCGCCAGGCTCCAGGCGAGGGGCTGGAGTGGG
TACGAAGCAGCCACCAGGGCCACTGGTATCCCAGC TGGCAGCTATATGGTTTGATGCAAGTGATAAATACT
CAGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCAC ATGCAGACGCCGTGAAGGGCCGATTCACCATCTCCA
NA
TCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGC GAGACAACTCCAAGAACACGCTGTATCTGCAAATG
AGTTTATTACTGTCAGCAGTATAACAACTGGCCTCT AACAGCCTGAGAGCCGAGGACACGGCTGTGTATTA
00
n
.7r CACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
CTGTGCGAGAGATTTGGCGATTTTTGGAGTGGTCCC 1-3
,-
fl
CGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTC
cp
o n.)
PI TAGT
(SEQ ID NO: 837) (SEQ ID NO: 838)
o
oe
'a
oe
cA
oe
A-2164-W0- P CT
EIVMTQ SP ATL SVSPGERATL SCRASQSVHSHLAWYQ QVQLVE SGGGVVQPGRSLRL
SCAASGFTFSNYGMHW
QKP GQAPRLLIYEAATRATGIP ARF S GS GS GTEFTL TI S VRQAP GE GLEWVAAIWFD
ASDKYYADAVKGRFTI SR
AA SLQSEDFAVYYCQQYNNWPLTFGGGTKVEIK
DNSKNTLYLQMNSLRAEDTAVYYCARDLAIFGVVPD 0
YWGQGTLVTVSS
n.)
o
(SEQ ID NO: 839) (SEQ ID NO: 840)
oe
i-J
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGT
c,.)
--.1
GTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGG CCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGC
o
--.1
GCCAGTCAGAGTGTTGATGTCAACTTAGCCTGGTAC ATCTGGATTCACCTTCAGTAACTATGGCATGCACTG
CAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATC GGTCCGCCAGGCTCCAGGCGAGGGGCTGGAGTGGG
TACGAAGCAGCCACCAGGGCCACTGGTATCCCAGC TGGCAGCTATATGGTTTGATGCAAGTGATAAATACT
CAGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCAC ATGCAGACGCCGTGAAGGGCCGATTCACCATCTCCA
NA
TCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGC GAGACAACTCCAAGAACACGCTGTATCTGCAAATG
AGTTTATTACTGTCAGCAGTATAACCAGTGGCCTCT AACAGCCTGAGAGCCGAGGACACGGCTGTGTATTA
CACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA CTGTGCGAGAGATTTGGCGATTTTTGGAGTGGTCCC
CGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTC
TAGT
p
(SEQ ID NO: 841) (SEQ ID NO: 842)
.
L.
EIVMTQ SP ATL SVSPGERATL SCRASQSVDVNLAWYQ QVQLVE SGGGVVQPGRSLRL
SCAASGFTFSNYGMHW "
,
N QKP GQAPRLLIYEAATRATGIP ARF S GS GS GTEFTL TI S VRQAP GE GLEWVAAIWFD
ASDKYYADAVKGRFTI SR .
f el o AA SLQSEDFAVYYCQQYNQWPLTFGGGTKVEIK
DNSKNTLYLQMNSLRAEDTAVYYCARDLAIFGVVPD
PI YWGQGTLVTVSS
(SEQ ID NO: 834) (SEQ ID NO: 844)
,
L.
,
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGT
GTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGG CCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGC
GCCAGTCAGAGTGTTGATGTCCACTTAGCCTGGTAC ATCTGGATTCACCTTCAGTAACTATGGCATGCACTG
CAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATC GGTCCGCCAGGCTCCAGGCGAGGGGCTGGAGTGGG
TACGAAGCAGCCACCAGGGCCACTGGTATCCCAGC TGGCAGCTATATGGTTTGATGCAAGTGATAAATACT
CAGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCAC ATGCAGACGCCGTGAAGGGCCGATTCACCATCTCCA
NA
TCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGC GAGACAACTCCAAGAACACGCTGTATCTGCAAATG
AGTTTATTACTGTCAGCAGTATAACCAGTGGCCTCT AACAGCCTGAGAGCCGAGGACACGGCTGTGTATTA
00
n
,- CACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
CTGTGCGAGAGATTTGGCGATTTTTGGAGTGGTCCC 1-3
.7r
fl
CGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTC
cp
o n.)
PI TAGT
(SEQ ID NO: 845) (SEQ ID NO: 846)
o
oe
'a
oe
cA
oe
61
A-2164-W0- P CT
EIVMTQ SP ATL SVSPGERATL SCRASQSVDVHLAWYQ QVQLVE SGGGVVQPGRSLRL
SCAASGFTFSNYGMHW
QKP GQAPRLLIYEAATRATGIP ARF S GS GS GTEFTL TI S VRQAP GE GLEWVAAIWFD
ASDKYYADAVKGRFTI SR
AA SLQSEDFAVYYCQQYNQWPLTFGGGTKVEIK
DNSKNTLYLQMNSLRAEDTAVYYCARDLAIFGVVPD 0
YWGQGTLVTVSS
n.)
o
(SEQ ID NO: 847) (SEQ ID NO: 848)
oe
i-J
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGT
c,.)
--.1
GTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGG CCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGC
o
--.1
GCCAGTCAGAGTGTTTTTGAACACTTAGCCTGGTAC ATCTGGATTCACCTTCAGTAACTATGGCATGCACTG
CAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATC GGTCCGCCAGGCTCCAGGCGAGGGGCTGGAGTGGG
TACGAAGCAGCCACCAGGGCCACTGGTATCCCAGC TGGCAGCTATATGGTTTGATGCAAGTGATAAATACT
CAGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCAC ATGCAGACGCCGTGAAGGGCCGATTCACCATCTCCA
NA
TCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGC GAGACAACTCCAAGAACACGCTGTATCTGCAAATG
AGTTTATTACTGTCAGCAGTATAACAACTGGCCTCT AACAGCCTGAGAGCCGAGGACACGGCTGTGTATTA
CACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA CTGTGCGAGAGATATTGCGATTTTTGGAGTGTTTCC
CGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTC
TAGT
p
(SEQ ID NO: 849) (SEQ ID NO: 850)
.
L.
EIVMTQ SP ATL SV SP GERATL SCRASQ SVFEHL AWYQ QVQLVE SGGGVVQPGRSLRL
SCAASGFTFSNYGMHW "
,
QKP GQAPRLLIYEAATRATGIP ARF S GS GS GTEFTL TI S VRQAP GE GLEWVAAIWFD
ASDKYYADAVKGRFTI SR .
o N,
'1 o AA SLQSEDFAVYYCQQYNNWPLTFGGGTKVEIK
DNSKNTLYLQMNSLRAEDTAVYYCARDIAIFGVFPDY
PI WGQGTLVTVSS
(SEQ ID NO: 851) (SEQ ID NO: 852)
,
L.
,
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGT
GTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGG CCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGC
GCCAGTCAGAGTGTTTTTGAACACTTAGCCTGGTAC ATCTGGATTCACCTTCAGTAACTATGGCATGCACTG
CAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATC GGTCCGCCAGGCTCCAGGCGAGGGGCTGGAGTGGG
TACGAAGCAGCCACCAGGGCCACTGGTATCCCAGC TGGCAGCTATATGGTTTGATGCAAGTGATAAATACT
CAGGGTCAGTGGCAGTGGGTCTGGGACAGAGTTCA ATGCAGACGCCGTGAAGGGCCGATTCACCATCTCCA
NA
CTCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTG GAGACAACTCCAAGAACACGCTGTATCTGCAAATG
CAGTTTATTACTGTCAGCAGTATAACAACTGGCCTC AACAGCCTGAGAGCCGAGGACACGGCTGTGTATTA
00
n
TCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA CTGTGCGAGAGATATTGCGATTTTTGGAGTGTTTCC
1-3
o
`z.
CGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTC
cp
o n.)
PI TAGT
(SEQ ID NO: 853) (SEQ ID NO: 854)
o
oe
'a
oe
cA
oe
62
A-2164-WO-PCT
EIVMTQ SP ATL SV SP GERATL SCRASQ SVFEHL AWYQ QVQLVE SGGGVVQPGRSLRL
SCAASGFTFSNYGMHW
QKP GQAPRLLIYEAATRATGIP ARVS GS GS GTEFTL TI S VRQAP GE GLEWVAAIWFD
ASDKYYADAVKGRFTI SR
AA SLQSEDFAVYYCQQYNNWPLTFGGGTKVEIK
DNSKNTLYLQMNSLRAEDTAVYYCARDIAIFGVFPDY 0
WGQGTLVTVSS
n.)
o
(SEQ ID NO: 855) (SEQ ID NO: 856)
oe
i-J
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGT
c,.)
--.1
GTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGG CCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGC
o
--.1
GCCAGTCAGAGTGTTTTCGAACACTTAGCCTGGTAC ATCTGGATTCACCTTCAGTAACTATGGCATGCACTG
CAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATC GGTCCGCCAGGCTCCAGGCGAGGGGCTGGAGTGGG
TACGAAGCAGCCACCAGGGCCACTGGTATCCCAGC TGGCAGCTATATGGTTTGATGCAAGTGATAAATACT
CAGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCAC ATGCAGACGCCGTGAAGGGCCGATTCACCATCTCCA
NA
TCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGC GAGACAACTCCAAGAACACGCTGTATCTGCAAATG
AGTTTATTACTGTCAGCAGTATAACCAGTGGCCTCT AACAGCCTGAGAGCCGAGGACACGGCTGTGTATTA
CACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA CTGTGCGAGAGATATTGCGATTTTTGGAGTGGTCCC
CGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTC
TAGT
p
(SEQ ID NO: 857) (SEQ ID NO: 858)
.
L.
EIVMTQ SP ATL SV SP GERATL SCRASQ SVFEHL AWYQ QVQLVE SGGGVVQPGRSLRL
SCAASGFTFSNYGMHW "
,
in QKP GQAPRLLIYEAATRATGIP ARF S GS GS GTEFTL TI S VRQAP GE GLEWVAAIWFD
ASDKYYADAVKGRFTI SR .
N,
n o AA SLQSEDFAVYYCQQYNQWPLTFGGGTKVEIK
DNSKNTLYLQMNSLRAEDTAVYYCARDIAIFGVVPDY
PI WGQGTLVTVSS
(SEQ ID NO: 859) (SEQ ID NO: 860)
,
L.
,
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGT
GTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGG CCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGC
GCCAGTCAGAGTGTTCTGGAACACTTAGCCTGGTAC ATCTGGATTCACCTTCAGTAACTATGGCATGCACTG
CAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATC GGTCCGCCAGGCTCCAGGCGAGGGGCTGGAGTGGG
TACGAAGCAGCCACCAGGGCCACTGGTATCCCAGC TGGCAGCTATATGGTTTGATGCAAGTGATAAATACT
CAGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCAC ATGCAGACGCCGTGAAGGGCCGATTCACCATCTCCA
NA
TCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGC GAGACAACTCCAAGAACACGCTGTATCTGCAAATG
AGTTTATTACTGTCAGCAGTATAACAACTGGCCTCT AACAGCCTGAGAGCCGAGGACACGGCTGTGTATTA
00
n
f 9) CACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
CTGTGCGAGAGATATTGCGATTTTTGGAGTGGTCCC 1-3
.7r
n
CGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTC
cp
o n.)
PI TAGT
(SEQ ID NO: 861) (SEQ ID NO: 862)
o
oe
'a
oe
cA
oe
63
A-2164-WO-PCT
EIVMTQ SP ATL SV SP GERATL SCRASQ SVLEHLAWYQ QVQLVE SGGGVVQPGRSLRL
SCAASGFTFSNYGMHW
QKP GQAPRLLIYEAATRATGIP ARF S GS GS GTEFTL TI S VRQAP GE GLEWVAAIWFD
ASDKYYADAVKGRFTI SR
AA SLQSEDFAVYYCQQYNNWPLTFGGGTKVEIK
DNSKNTLYLQMNSLRAEDTAVYYCARDIAIFGVVPDY 0
WGQGTLVTVSS
n.)
o
(SEQ ID NO: 863) (SEQ ID NO: 864)
oe
i-J
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGT
c,.)
--.1
GTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGG CCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGC
o
--.1
GCCAGTCAGAGTGTTGATAGACACTTAGCCTGGTAC ATCTGGATTCACCTTCAGTAACTATGGCATGCACTG
CAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATC GGTCCGCCAGGCTCCAGGCGAGGGGCTGGAGTGGG
TACGAAGCAGCCACCAGGGCCACTGGTATCCCAGC TGGCAGCTATATGGTTTGATGCAAGTGATAAATACT
CAGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCAC ATGCAGACGCCGTGAAGGGCCGATTCACCATCTCCA
NA
TCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGC GAGACAACTCCAAGAACACGCTGTATCTGCAAATG
AGTTTATTACTGTCAGCAGTATAACCAGTGGCCTCT AACAGCCTGAGAGCCGAGGACACGGCTGTGTATTA
CACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA CTGTGCGAGAGATATTGCGATTTTTGGAGTGTTTCC
CGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTC
TAGT
p
(SEQ ID NO: 865) (SEQ ID NO: 866)
.
L.
EIVMTQ SP ATL SV SP GERATL SCRASQ SVDRHLAWYQ QVQLVE SGGGVVQPGRSLRL
SCAASGFTFSNYGMHW "
,
f e) QKP GQAPRLLIYEAATRATGIP ARF S GS GS GTEFTL TI S VRQAP GE GLEWVAAIWFD
ASDKYYADAVKGRFTI SR .
N,
'el o AA SLQSEDFAVYYCQQYNQWPLTFGGGTKVEIK
DNSKNTLYLQMNSLRAEDTAVYYCARDIAIFGVFPDY
PI WGQGTLVTVSS
(SEQ ID NO: 867) (SEQ ID NO: 868)
,
L.
,
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGT
GTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGG CCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGC
GCCAGTCAGAGTGTTAACCGGCACTTAGCCTGGTAC ATCTGGATTCACCTTCAGTAACTATGGCATGCACTG
CAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATC GGTCCGCCAGGCTCCAGGCGAGGGGCTGGAGTGGG
TACGAAGCAGCCACCAGGGCCACTGGTATCCCAGC TGGCAGCTATATGGTTTGATGCAAGTGATAAATACT
CAGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCAC ATGCAGACGCCGTGAAGGGCCGATTCACCATCTCCA
NA
TCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGC GAGACAACTCCAAGAACACGCTGTATCTGCAAATG
AGTTTATTACTGTCAGCAGTATCAGCAGTGGCCTCT AACAGCCTGAGAGCCGAGGACACGGCTGTGTATTA
00
n
N CACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
CTGTGCGAGAGATATTGCGATTTTTGGAGTGTTTCC 1-3
,-
fl
CGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTC
cp
o n.)
PI TAGT
(SEQ ID NO: 869) (SEQ ID NO: 870)
o
oe
'a
oe
cA
oe
64
A-2164-WO-PCT
EIVMTQSPATLSVSPGERATLSCRASQSVNRHLAWYQ QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMHW
QKPGQAPRLLIYEAATRATGIPARFSGSGSGTEFTLTIS VRQAPGEGLEWVAAIWFDASDKYYADAVKGRFTISR
AA SLQSEDFAVYYCQQYQQWPLTFGGGTKVEIK
DNSKNTLYLQMNSLRAEDTAVYYCARDIAIFGVFPDY 0
WGQGTLVTVSS
n.)
o
(SEQ ID NO: 871) (SEQ ID NO: 872)
oe
i-J
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGT
c,.)
--.1
GTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGG CCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGC
o
--.1
GCCAGTCAGAGTGTTAACGTACACTTAGCCTGGTAC ATCTGGATTCACCTTCAGTAACTATGGCATGCACTG
CAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATC GGTCCGCCAGGCTCCAGGCGAGGGGCTGGAGTGGG
TACCAGGCAGCCACCAGGGCCACTGGTATCCCAGCC TGGCAGCTATATGGTTTGATGCAAGTGATAAATACT
AGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCACT ATGCAGACGCCGTGAAGGGCCGATTCACCATCTCCA
NA
CTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGCA GAGACAACTCCAAGAACACGCTGTATCTGCAAATG
GTTTATTACTGTCAGCAGTATAACCAGTGGCCTCTC AACAGCCTGAGAGCCGAGGACACGGCTGTGTATTA
ACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
CTGTGCGAGAGATATTGCGATTTTTGGAGTGTTTCC
CGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTC
TAGT
p
(SEQ ID NO: 873) (SEQ ID NO: 874)
.
L.
EIVMTQSPATLSVSPGERATLSCRASQSVNVHLAWYQ QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMHW
"
,
,- QKPGQAPRLLIYQAATRATGIPARFSGSGSGTEFTLTIS
VRQAPGEGLEWVAAIWFDASDKYYADAVKGRFTISR .
N,
n o AA SLQSEDFAVYYCQQYNQWPLTFGGGTKVEIK
DNSKNTLYLQMNSLRAEDTAVYYCARDIAIFGVFPDY
PI WGQGTLVTVSS
(SEQ ID NO: 875) (SEQ ID NO: 876)
,
L.
,
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGT
GTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGG CCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGC
GCCAGTCAGAGTGTTCTGACGCACTTAGCCTGGTAC ATCTGGATTCACCTTCAGTAACTATGGCATGCACTG
CAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATC GGTCCGCCAGGCTCCAGGCGAGGGGCTGGAGTGGG
TACGAAGCAGCCACCAGGGCCACTGGTATCCCAGC TGGCAGCTATATGGTTTGATGCAAGTGATAAATACT
CAGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCAC ATGCAGACGCCGTGAAGGGCCGATTCACCATCTCCA
NA
TCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGC GAGACAACTCCAAGAACACGCTGTATCTGCAAATG
AGTTTATTACTGTCAGCAGTATCAGAACTGGCCTCT AACAGCCTGAGAGCCGAGGACACGGCTGTGTATTA
00
n
CACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA CTGTGCGAGAGATATTGCGATTTTTGGAGTGATCCC
1-3
o
n
CGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTC
cp
o n.)
PI TAGT
(SEQ ID NO: 877) (SEQ ID NO: 878)
o
oe
'a
oe
cA
oe
A-2164-WO-PCT
EIVMTQ SP ATL SV SP GERATL SCRASQ SVLTHLAWYQ QVQLVE SGGGVVQPGRSLRL
SCAASGFTFSNYGMHW
QKP GQAPRLLIYEAATRATGIP ARF S GS GS GTEFTL TI S VRQAP GE GLEWVAAIWFD
ASDKYYADAVKGRFTI SR
AA SLQSEDFAVYYCQQYQNWPLTFGGGTKVEIK
DNSKNTLYLQMNSLRAEDTAVYYCARDIAIFGVIPDY 0
WGQGTLVTVSS
n.)
o
(SEQ ID NO: 879) (SEQ ID NO: 880)
oe
i-J
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGT
c,.)
--.1
GTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGG CCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGC
o
--.1
GCCAGTCAGAGTGTTCTGACGCACTTAGCCTGGTAC ATCTGGATTCACCTTCAGTAACTATGGCATGCACTG
CAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATC GGTCCGCCAGGCTCCAGGCGAGGGGCTGGAGTGGG
TACGAAGCAGCCACCAGGGCCACTGGTATCCCAGC TGGCAGCTATATGGTTTGATGCAAGTGATAAATACT
CAGGGTCAGTGGCAGTGGGTCTGGGACAGAGTTCA ATGCAGACGCCGTGAAGGGCCGATTCACCATCTCCA
NA
CTCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTG GAGACAACTCCAAGAACACGCTGTATCTGCAAATG
CAGTTTATTACTGTCAGCAGTATCAGAACTGGCCTC AACAGCCTGAGAGCCGAGGACACGGCTGTGTATTA
TCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA CTGTGCGAGAGATATTGCGATTTTTGGAGTGATCCC
CGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTC
TAGT
p
(SEQ ID NO: 881) (SEQ ID NO: 882)
.
L.
EIVMTQ SP ATL SV SP GERATL SCRASQ SVLTHLAWYQ QVQLVE SGGGVVQPGRSLRL
SCAASGFTFSNYGMHW "
,
QKP GQAPRLLIYEAATRATGIP ARVS GS GS GTEFTL TI S VRQAP GE GLEWVAAIWFD
ASDKYYADAVKGRFTI SR .
o N,
AA SLQSEDFAVYYCQQYQNWPLTFGGGTKVEIK
DNSKNTLYLQMNSLRAEDTAVYYCARDIAIFGVIPDY
PI WGQGTLVTVSS
(SEQ ID NO: 883) (SEQ ID NO: 884)
,
L.
,
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGT
GTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGG CCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGC
GCCAGTCAGAGTGTTAGCAGCAACTTAGCCTGGTAC ATCTGGATTCACCTTCAGTAACTATGGCATGCACTG
CAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATC GGTCCGCCAGGCTCCAGGCGAGGGGCTGGAGTGGG
TATGGTGCAGCCACCAGGGCCACTGGTATCCCAGCC TGGCAGCTATATGGTTTGATGCAAGTGATAAATACT
AGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCACT ATGCAGACGCCGTGAAGGGCCGATTCACCATCTCCA
NA
CTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGCA GAGACAACTCCAAGAACACGCTGTATCTGCAAATG
GTTTATTACTGTCAGCAGTATAATAACTGGCCTCTC AACAGCCTGAGAGCCGAGGACACGGCTGTGTATTA
00
n
N ACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA CTGTGCGAGAGATTTGGCGATTTTTGGAGTGGTCCC
1-3
.7r
n
CGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTC
cp
o n.)
PI TAGT
(SEQ ID NO: 885) (SEQ ID NO: 886)
o
oe
'a
oe
cA
oe
66
A-2164-W0- P CT
EIVMTQ SP ATL SVSPGERATLSCRASQSVS SNLAWYQQ QVQLVE SGGGVVQPGRSLRL
SCAASGFTFSNYGMHW
KPGQAPRLLIYGAATRATGIPARFS GS GS GTEFTLTI S S VRQAP GE GLEWVAAIWFD
ASDKYYADAVKGRFTI SR
AA LQSEDFAVYYCQQYNNWPLTFGGGTKVEIK
DNSKNTLYLQMNSLRAEDTAVYYCARDLAIFGVVPD 0
YWGQGTLVTVSS
n.)
o
(SEQ ID NO: 887) (SEQ ID NO: 888)
oe
i-J
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGT
c,.)
--.1
GTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGG CCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGC
o
--.1
GCCAGTCAGAGTGTTAGCAGCAACTTAGCCTGGTAC ATCTGGATTCACCTTCAGTAACTATGGCATGCACTG
CAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATC GGTCCGCCAGGCTCCAGGCGAGGGGCTGGAGTGGG
TATGGTGCAGCCACCAGGGCCACTGGTATCCCAGCC TGGCAGCTATATGGTTTGATGCAAGTGATAAATACT
AGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCACT ATGCAGACGCCGTGAAGGGCCGATTCACCATCTCCA
NA
CTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGCA GAGACAACTCCAAGAACACGCTGTATCTGCAAATG
GTTTATTACTGTCAGCAGTATAATAACTGGCCTCTC AACAGCCTGAGAGCCGAGGACACGGCTGTGTATTA
ACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
CTGTGCGAGAGATCAGGCGATTTTTGGAGTGGTCCC
CGATTACTGGGGCCAGGGAACCCTGGTCACCGTGTC
TAGT
p
(SEQ ID NO: 889) (SEQ ID NO: 890)
.
L.
EIVMTQ SP ATL SVSPGERATL SCRASQSVS SNLAWYQQ QVQLVE SGGGVVQPGRSLRL
SCAASGFTFSNYGMHW "
,
co KPGQAPRLLIYGAATRATGIPARFS GS GS GTEFTLTI S S VRQAP GE GLEWVAAIWFD
ASDKYYADAVKGRFTI SR .
.7r
N,
n o AA LQSEDFAVYYCQQYNNWPLTFGGGTKVEIK
DNSKNTLYLQMNSLRAEDTAVYYCARDQAIFGVVPD
PI YWGQGTLVTVSS
(SEQ ID NO: 891) (SEQ ID NO: 892)
,
L.
,
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGT
GTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGG CCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGC
GCCAGTCAGAGTGTTAGCAGCAACTTAGCCTGGTAC ATCTGGATTCACCTTCAGTAACTATGGCATGCACTG
CAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATC GGTCCGCCAGGCTCCAGGCGAGGGGCTGGAGTGGG
TATGGTGCAGCCACCAGGGCCACTGGTATCCCAGCC TGGCAGCTATATGGTTTGATGCAAGTGATAAATACT
AGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCACT ATGCAGACGCCGTGAAGGGCCGATTCACCATCTCCA
NA
CTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGCA GAGACAACTCCAAGAACACGCTGTATCTGCAAATG
GTTTATTACTGTCAGCAGTATAATAACTGGCCTCTC AACAGCCTGAGAGCCGAGGACACGGCTGTGTATTA
00
n
ACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA CTGTGCGAGAGATATTGCGATTTTTGGAGTGGTCCC
1-3
.7r
n
CGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTC
cp
o n.)
PI TAGT
(SEQ ID NO: 893) (SEQ ID NO: 894)
o
oe
'a
oe
cA
oe
67
A-2164-W0- P CT
EIVMTQSPATL SVSPGERATLSCRASQSVSSNLAWYQQ QVQLVE SGGGVVQPGRSLRL SCAASGFTFSNYGMHW
KPGQAPRLLIYGAATRATGIPARFS GS GS GTEFTLTI S S VRQAP GE GLEWVAAIWFD
ASDKYYADAVKGRFTI SR
AA LQSEDFAVYYCQQYNNWPLTFGGGTKVEIK
DNSKNTLYLQMNSLRAEDTAVYYCARDIAIFGVVPDY 0
WGQGTLVTVSS
n.)
o
(SEQ ID NO: 895) (SEQ ID NO: 896)
oe
i-J
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGT
c,.)
--.1
GTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGG CCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGC
o
--.1
GCCAGTCAGAGTGTTAGCAGCAACTTAGCCTGGTAC ATCTGGATTCACCTTCAGTAACTATGGCATGCACTG
CAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATC GGTCCGCCAGGCTCCAGGCGAGGGGCTGGAGTGGG
TATGGTGCAGCCACCAGGGCCACTGGTATCCCAGCC TGGCAGCTATATGGTTTGATGCAAGTGATAAATACT
AGGGTCAGTGGCAGTGGGTCTGGGACAGAGTTCAC ATGCAGACGCCGTGAAGGGCCGATTCACCATCTCCA
NA
TCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGC GAGACAACTCCAAGAACACGCTGTATCTGCAAATG
AGTTTATTACTGTCAGCAGTATAATAACTGGCCTCT AACAGCCTGAGAGCCGAGGACACGGCTGTGTATTA
CACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA CTGTGCGAGAGATTTGGCGATTTTTGGAGTGGTCCC
CGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTC
TAGT
p
(SEQ ID NO: 897) (SEQ ID NO: 898)
.
L.
EIVMTQSPATL SVSPGERATL SCRASQSVSSNLAWYQQ QVQLVE SGGGVVQPGRSLRL
SCAASGFTFSNYGMHW "
,
N KP GQAPRLLIYGAATRATGIPARVS GS GS GTEFTL TI S S VRQAP GE GLEWVAAIWFD
ASDKYYADAVKGRFTI SR .
.7r
N,
AA LQSEDFAVYYCQQYNNWPLTFGGGTKVEIK
DNSKNTLYLQMNSLRAEDTAVYYCARDLAIFGVVPD
PI YWGQGTLVTVSS
(SEQ ID NO: 899) (SEQ ID NO: 900)
,
L.
,
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGT
GTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGG CCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGC
GCCAGTCAGAGTGTTAGCAGCAACTTAGCCTGGTAC ATCTGGATTCACCTTCAGTAACTATGGCATGCACTG
CAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATC GGTCCGCCAGGCTCCAGGCGAGGGGCTGGAGTGGG
TATGAAGCAGCCACCAGGGCCACTGGTATCCCAGCC TGGCAGCTATATGGTTTGATGCAAGTGATAAATACT
AGGGTCAGTGGCAGTGGGTCTGGGACAGAGTTCAC ATGCAGACGCCGTGAAGGGCCGATTCACCATCTCCA
NA
TCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGC GAGACAACTCCAAGAACACGCTGTATCTGCAAATG
AGTTTATTACTGTCAGCAGTATAATAACTGGCCTCT AACAGCCTGAGAGCCGAGGACACGGCTGTGTATTA
00
n
c, CACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
CTGTGCGAGAGATCAGGCGATTTTTGGAGTGGTCCC 1-3
.7r
`z.
CGATTACTGGGGCCAGGGAACCCTGGTCACCGTGTC
cp
o n.)
PI TAGT
(SEQ ID NO: 901) (SEQ ID NO: 902)
o
oe
'a
oe
cA
oe
68
A-2164-WO-PCT
EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQ QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMHW
KPGQAPRLLIYEAATRATGIPARVSGSGSGTEFTLTISS VRQAPGEGLEWVAAIWFDASDKYYADAVKGRFTISR
AA LQSEDFAVYYCQQYNNWPLTFGGGTKVEIK
DNSKNTLYLQMNSLRAEDTAVYYCARDQAIFGVVPD 0
YWGQGTLVTVSS
n.)
o
(SEQ ID NO: 903) (SEQ ID NO: 904)
oe
i-J
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGT
c,.)
--.1
GTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGG CCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGC
o
--.1
GCCAGTCAGAGTGTTGATGTTAACTTAGCCTGGTAC ATCTGGATTCACCTTCAGTAACTATGGCATGCACTG
CAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATC GGTCCGCCAGGCTCCAGGCGAGGGGCTGGAGTGGG
TACAACGCAGCCACCAGGGCCACTGGTATCCCAGCC TGGCAGCTATATGGTTTGATGCAAGTGATAAATACT
AGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCACT ATGCAGACGCCGTGAAGGGCCGATTCACCATCTCCA
NA
CTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGCA GAGACAACTCCAAGAACACGCTGTATCTGCAAATG
GTTTATTACTGTCAGCAGTATCAGAACTGGCCTCTC AACAGCCTGAGAGCCGAGGACACGGCTGTGTATTA
ACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
CTGTGCGAGAGATTTGGCGATTTTTGGAGTGGTCCC
CGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTC
TAGT
p
(SEQ ID NO: 905) (SEQ ID NO: 906)
.
L.
EIVMTQSPATLSVSPGERATLSCRASQSVDVNLAWYQ QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMHW
"
,
in QKPGQAPRLLIYNAATRATGIPARFSGSGSGTEFTLTIS
VRQAPGEGLEWVAAIWFDASDKYYADAVKGRFTISR .
o N,
'1 o AA SLQSEDFAVYYCQQYQNWPLTFGGGTKVEIK
DNSKNTLYLQMNSLRAEDTAVYYCARDLAIFGVVPD
PI YWGQGTLVTVSS
(SEQ ID NO: 907) (SEQ ID NO: 908)
,
L.
,
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGT
GTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGG CCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGC
GCCAGTCAGAGTGTTGATGTTAACTTAGCCTGGTAC ATCTGGATTCACCTTCAGTAACTATGGCATGCACTG
CAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATC GGTCCGCCAGGCTCCAGGCGAGGGGCTGGAGTGGG
TACAACGCAGCCACCAGGGCCACTGGTATCCCAGCC TGGCAGCTATATGGTTTGATGCAAGTGATAAATACT
AGGGTCAGTGGCAGTGGGTCTGGGACAGAGTTCAC ATGCAGACGCCGTGAAGGGCCGATTCACCATCTCCA
NA
TCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGC GAGACAACTCCAAGAACACGCTGTATCTGCAAATG
AGTTTATTACTGTCAGCAGTATCAGAACTGGCCTCT AACAGCCTGAGAGCCGAGGACACGGCTGTGTATTA
00
n
in CACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
CTGTGCGAGAGATTTGGCGATTTTTGGAGTGGTCCC 1-3
o
`z.
CGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTC
cp
o n.)
PI TAGT
(SEQ ID NO: 909) (SEQ ID NO: 910)
o
oe
'a
oe
cA
oe
69
A-2164-WO-PCT
EIVMTQSPATLSVSPGERATLSCRASQSVDVNLAWYQ QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMHW
QKPGQAPRLLIYNAATRATGIPARVSGSGSGTEFTLTIS VRQAPGEGLEWVAAIWFDASDKYYADAVKGRFTISR
AA SLQSEDFAVYYCQQYQNWPLTFGGGTKVEIK
DNSKNTLYLQMNSLRAEDTAVYYCARDLAIFGVVPD 0
YWGQGTLVTVSS
n.)
o
(SEQ ID NO: 911) (SEQ ID NO: 912)
oe
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGT
c,.)
--.1
GTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGG CCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGC
o
--.1
GCCAGTCAGAGTGTTCATACGAACTTAGCCTGGTAC ATCTGGATTCACCTTCAGTAACTATGGCATGCACTG
CAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATC GGTCCGCCAGGCTCCAGGCGAGGGGCTGGAGTGGG
TACAACGCAGCCACCAGGGCCACTGGTATCCCAGCC TGGCAGCTATATGGTTTGATGCAAGTGATAAATACT
AGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCACT ATGCAGACGCCGTGAAGGGCCGATTCACCATCTCCA
NA
CTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGCA GAGACAACTCCAAGAACACGCTGTATCTGCAAATG
GTTTATTACTGTCAGCAGTATCAGAACTGGCCTCTC AACAGCCTGAGAGCCGAGGACACGGCTGTGTATTA
ACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
CTGTGCGAGAGATATTGCGATTTTTGGAGTGGTCCC
CGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTC
TAGT
p
(SEQ ID NO: 913) (SEQ ID NO: 914)
.
L.
EIVMTQSPATLSVSPGERATLSCRASQSVHTNLAWYQ QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMHW
"
,
o
QKPGQAPRLLIYNAATRATGIPARFSGSGSGTEFTLTIS VRQAPGEGLEWVAAIWFDASDKYYADAVKGRFTISR
.
.7r
N,
n o AA SLQSEDFAVYYCQQYQNWPLTFGGGTKVEIK
DNSKNTLYLQMNSLRAEDTAVYYCARDIAIFGVVPDY
PI WGQGTLVTVSS
(SEQ ID NO: 915) (SEQ ID NO: 916)
,
L.
,
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGT
GTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGG CCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGC
GCCAGTCAGAGTGTTAACCTGAACTTAGCCTGGTAC ATCTGGATTCACCTTCAGTAACTATGGCATGCACTG
CAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATC GGTCCGCCAGGCTCCAGGCGAGGGGCTGGAGTGGG
TACCAGGCAGCCACCAGGGCCACTGGTATCCCAGCC TGGCAGCTATATGGTTTGATGCAAGTGATAAATACT
AGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCACT ATGCAGACGCCGTGAAGGGCCGATTCACCATCTCCA
NA
CTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGCA GAGACAACTCCAAGAACACGCTGTATCTGCAAATG
GTTTATTACTGTCAGCAGTATAACCAGTGGCCTCTC AACAGCCTGAGAGCCGAGGACACGGCTGTGTATTA
00
n
.7r ACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA CTGTGCGAGAGATTTGGCGATTTTTGGAGTGGTCCC
1-3
f 9)
fl
CGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTC
cp
o n.)
PI TAGT
(SEQ ID NO: 917) (SEQ ID NO: 918)
o
oe
'a
oe
cA
oe
A-2164-WO-PCT
EIVMTQ SP ATL SVSPGERATL SCRASQSVNLNLAWYQ QVQLVE SGGGVVQPGRSLRL
SCAASGFTFSNYGMHW
QKP GQAPRLLIYQAATRATGIPARF S GS GS GTEFTLTI S VRQAP GE GLEWVAAIWFD
ASDKYYADAVKGRFTI SR
AA SLQSEDFAVYYCQQYNQWPLTFGGGTKVEIK
DNSKNTLYLQMNSLRAEDTAVYYCARDLAIFGVVPD 0
YWGQGTLVTVSS
n.)
o
(SEQ ID NO: 919) (SEQ ID NO: 920)
oe
i-J
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGT
c,.)
--.1
GTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGG CCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGC
o
--.1
GCCAGTCAGAGTGTTTTCCAGAACTTAGCCTGGTAC ATCTGGATTCACCTTCAGTAACTATGGCATGCACTG
CAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATC GGTCCGCCAGGCTCCAGGCGAGGGGCTGGAGTGGG
TACCAGGCAGCCACCAGGGCCACTGGTATCCCAGCC TGGCAGCTATATGGTTTGATGCAAGTGATAAATACT
AGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCACT ATGCAGACGCCGTGAAGGGCCGATTCACCATCTCCA
NA
CTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGCA GAGACAACTCCAAGAACACGCTGTATCTGCAAATG
GTTTATTACTGTCAGCAGTATAACCAGTGGCCTCTC AACAGCCTGAGAGCCGAGGACACGGCTGTGTATTA
ACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
CTGTGCGAGAGATATTGCGATTTTTGGAGTGGTCCC
CGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTC
TAGT
p
(SEQ ID NO: 921) (SEQ ID NO: 922)
.
L.
EIVMTQ SPATL SVSPGERATL SCRASQSVFQNLAWYQ QVQLVE SGGGVVQPGRSLRL
SCAASGFTFSNYGMHW "
,
o, QKP GQAPRLLIYQAATRATGIPARF S GS GS GTEFTLTI S VRQAP GE GLEWVAAIWFD
ASDKYYADAVKGRFTI SR .
f el o AA SLQSEDFAVYYCQQYNQWPLTFGGGTKVEIK
DNSKNTLYLQMNSLRAEDTAVYYCARDIAIFGVVPDY
PI WGQGTLVTVSS
(SEQ ID NO: 923) (SEQ ID NO: 924)
,
L.
,
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGT
GTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGG CCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGC
GCCAGTCAGAGTGTTGATAGACACTTAGCCTGGTAC ATCTGGATTCACCTTCCAGAACTATGGCATGCACTG
CAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATC GGTCCGCCAGGCTCCAGGCGAGGGGCTGGAGTGGG
TACGAAGCAGCCACCAGGGCCACTGGTATCCCAGC TGGCAGCTATATGGTTTGATGCGTACGGTAAATACT
CAGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCAC ATGCAGACGCCGTGAAGGGCCGATTCACCATCTCCA
NA
TCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGC GAGACAACTCCAAGAACACGCTGTATCTGCAAATG
AGTTTATTACTGTCAGCAGTATAACCAGTGGCCTCT AACAGCCTGAGAGCCGAGGACACGGCTGTGTATTA
00
n
N CACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
CTGTGCGAGAGATCAGACGATTTTTGGAGTGGTCCC 1-3
o
fl
CGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTC
cp
o n.)
PI TAGT
(SEQ ID NO: 925) (SEQ ID NO: 926)
o
oe
'a
oe
cA
oe
71
A-2164-WO-PCT
EIVMTQ SP ATL SV SP GERATL SCRASQ SVDRHLAWYQ QVQLVESGGGVVQPGRSLRL
SCAASGFTFQNYGMHW
QKP GQAPRLLIYEAATRATGIPARF S GS GS GTEFTLTI S VRQAP GE GLEWVAAIWFD
AYGKYYADAVKGRFTI SR
AA SLQSEDFAVYYCQQYNQWPLTFGGGTKVEIK
DNSKNTLYLQMNSLRAEDTAVYYCARDQTIFGVVPD 0
YWGQGTLVTVSS
n.)
o
(SEQ ID NO: 927) (SEQ ID NO: 928)
oe
i-J
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGT
c,.)
--.1
GTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGG CCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGC
o
--.1
GCCAGTCAGAGTGTTGATAGACACTTAGCCTGGTAC ATCTGGATTCACCTTCCAGAACTATGGCATGCACTG
CAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATC GGTCCGCCAGGCTCCAGGCGAGGGGCTGGAGTGGG
TACGAAGCAGCCACCAGGGCCACTGGTATCCCAGC TGGCAGCTATATGGTTTGATGCGTACGGTAAATACT
CAGGGTCAGTGGCAGTGGGTCTGGGACAGAGTTCA ATGCAGACGCCGTGAAGGGCCGATTCACCATCTCCA
NA
CTCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTG GAGACAACTCCAAGAACACGCTGTATCTGCAAATG
CAGTTTATTACTGTCAGCAGTATAACCAGTGGCCTC AACAGCCTGAGAGCCGAGGACACGGCTGTGTATTA
TCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA CTGTGCGAGAGATCAGACGATTTTTGGAGTGGTCCC
CGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTC
TAGT
p
(SEQ ID NO: 929) (SEQ ID NO: 930)
.
L.
EIVMTQ SP ATL SV SP GERATL SCRASQ SVDRHLAWYQ
QVQLVESGGGVVQPGRSLRLSCAASGFTFQNYGMHW "
,
N QKP GQAPRLLIYEAATRATGIPARVS GS GS GTEFTLTI S VRQAP GE GLEWVAAIWFD
AYGKYYADAVKGRFTI SR .
o N,
AA SLQSEDFAVYYCQQYNQWPLTFGGGTKVEIK
DNSKNTLYLQMNSLRAEDTAVYYCARDQTIFGVVPD
PI YWGQGTLVTVSS
(SEQ ID NO: 931) (SEQ ID NO: 932)
,
L.
,
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGT
GTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGG CCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGC
GCCAGTCAGAGTGTTAACCGGCACTTAGCCTGGTAC ATCTGGATTCACCTTCCAGAACTATGGCATGCACTG
CAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATC GGTCCGCCAGGCTCCAGGCGAGGGGCTGGAGTGGG
TACGAAGCAGCCACCAGGGCCACTGGTATCCCAGC TGGCAGCTATATGGTTTGATGCGTACGGTAAATACT
CAGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCAC ATGCAGACGCCGTGAAGGGCCGATTCACCATCTCCA
NA
TCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGC GAGACAACTCCAAGAACACGCTGTATCTGCAAATG
AGTTTATTACTGTCAGCAGTATAACCAGTGGCCTCT AACAGCCTGAGAGCCGAGGACACGGCTGTGTATTA
00
n
,- CACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
CTGTGCGAGAGATAAGACGATTTTTGGAGTGGTCCC 1-3
n
CGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTC
cp
o n.)
PI TAGT
(SEQ ID NO: 933) (SEQ ID NO: 934)
o
oe
'a
oe
cA
oe
72
A-2164-WO-PCT
EIVMTQ SP ATL SV SP GERATL SCRASQ SVNRHLAWYQ QVQLVESGGGVVQPGRSLRL
SCAASGFTFQNYGMHW
QKP GQAPRLLIYEAATRATGIPARF S GS GS GTEFTLTI S VRQAP GE GLEWVAAIWFD
AYGKYYADAVKGRFTI SR
AA SLQSEDFAVYYCQQYNQWPLTFGGGTKVEIK
DNSKNTLYLQMNSLRAEDTAVYYCARDKTIFGVVPD 0
YWGQGTLVTVSS
n.)
o
(SEQ ID NO: 935) (SEQ ID NO: 936)
oe
i-J
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGT
c,.)
--.1
GTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGG CCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGC
o
--.1
GCCAGTCAGAGTGTTGAAAGACACTTAGCCTGGTAC ATCTGGATTCACCTTCCAGAACTATGGCATGCACTG
CAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATC GGTCCGCCAGGCTCCAGGCGAGGGGCTGGAGTGGG
TACGAAGCAGCCACCAGGGCCACTGGTATCCCAGC TGGCAGCTATATGGTTTGATGCGTACGGTAAATACT
CAGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCAC ATGCAGACGCCGTGAAGGGCCGATTCACCATCTCCA
NA
TCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGC GAGACAACTCCAAGAACACGCTGTATCTGCAAATG
AGTTTATTACTGTCAGCAGTATCAGCAGTGGCCTCT AACAGCCTGAGAGCCGAGGACACGGCTGTGTATTA
CACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA CTGTGCGAGAGATAAGACGATTTTTGGAGTGGTCCC
CGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTC
TAGT
p
(SEQ ID NO: 937) (SEQ ID NO: 938)
.
L.
EIVMTQ SP ATL SV SPGERATL SCRASQ SVERHLAWYQ QVQLVESGGGVVQPGRSLRL
SCAASGFTFQNYGMHW "
,
QKP GQAPRLLIYEAATRATGIPARF S GS GS GTEFTLTI S VRQAP GE GLEWVAAIWFD
AYGKYYADAVKGRFTI SR .
.7r
N,
n o AA SLQSEDFAVYYCQQYQQWPLTFGGGTKVEIK
DNSKNTLYLQMNSLRAEDTAVYYCARDKTIFGVVPD
PI YWGQGTLVTVSS
(SEQ ID NO: 939) (SEQ ID NO: 940)
,
L.
,
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGT
GTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGG CCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGC
GCCAGTCAGAGTGTTTTCAGACACTTAGCCTGGTAC ATCTGGATTCACCTTCAGTAACTATGGCATGCACTG
CAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATC GGTCCGCCAGGCTCCAGGCGAGGGGCTGGAGTGGG
TACGAAGCAGCCACCAGGGCCACTGGTATCCCAGC TGGCAGCTATATGGTTTGATGCGTACGGTAAATACT
CAGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCAC ATGCAGACGCCGTGAAGGGCCGATTCACCATCTCCA
NA
TCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGC GAGACAACTCCAAGAACACGCTGTATCTGCAAATG
AGTTTATTACTGTCAGCAGTATCAGAACTGGCCTCT AACAGCCTGAGAGCCGAGGACACGGCTGTGTATTA
00
n
c, CACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
CTGTGCGAGAGATAAGACGATTTTTGGAGTGGTCCC 1-3
,-
n
CGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTC
cp
o n.)
PI TAGT
(SEQ ID NO: 941) (SEQ ID NO: 942)
o
oe
'a
oe
cA
oe
73
A-2164-WO-PCT
EIVMTQ SP ATL SVSP GERATL SCRASQ SVFRHLAWYQ QVQLVE SGGGVVQPGRSLRL
SCAASGFTFSNYGMHW
QKP GQAPRLLIYEAATRATGIPARF S GS GS GTEFTLTI S VRQAP GE GLEWVAAIWFD
AYGKYYADAVKGRFTI SR
AA SLQSEDFAVYYCQQYQNWPLTFGGGTKVEIK
DNSKNTLYLQMNSLRAEDTAVYYCARDKTIFGVVPD 0
YWGQGTLVTVSS
n.)
o
(SEQ ID NO: 943) (SEQ ID NO: 944)
oe
i-J
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGT
c,.)
--.1
GTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGG CCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGC
o
--.1
GCCAGTCAGAGTGTTCTGAGTCACTTAGCCTGGTAC ATCTGGATTCACCTTCCAGAACTATGGCATGCACTG
CAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATC GGTCCGCCAGGCTCCAGGCGAGGGGCTGGAGTGGG
TACGAAGCAGCCACCAGGGCCACTGGTATCCCAGC TGGCAGCTATATGGTTTGATGCGTACGACAAATACT
CAGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCAC ATGCAGACGCCGTGAAGGGCCGATTCACCATCTCCA
NA
TCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGC GAGACAACTCCAAGAACACGCTGTATCTGCAAATG
AGTTTATTACTGTCAGCAGTATAACAACTGGCCTCT AACAGCCTGAGAGCCGAGGACACGGCTGTGTATTA
CACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA CTGTGCGAGAGATAAGTCGATTTTTGGAGTGGTCCC
CGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTC
TAGT
p
(SEQ ID NO: 945) (SEQ ID NO: 946)
.
L.
EIVMTQ SP ATL SV SP GERATL SCRASQ SVL SHLAWYQ QVQLVESGGGVVQPGRSLRL
SCAASGFTFQNYGMHW "
,
QKP GQAPRLLIYEAATRATGIPARF S GS GS GTEFTLTI S VRQAP GE GLEWVAAIWFD
AYDKYYADAVKGRFTI SR .
(I o AA SLQSEDFAVYYCQQYNNWPLTFGGGTKVEIK
DNSKNTLYLQMNSLRAEDTAVYYCARDKSIFGVVPD
PI YWGQGTLVTVSS
(SEQ ID NO: 947) (SEQ ID NO: 948)
,
L.
,
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGT
GTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGG CCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGC
GCCAGTCAGAGTGTTAACAGACACTTAGCCTGGTAC ATCTGGATTCACCTTCCAGAACTATGGCATGCACTG
CAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATC GGTCCGCCAGGCTCCAGGCGAGGGGCTGGAGTGGG
TACGAAGCAGCCACCAGGGCCACTGGTATCCCAGC TGGCAGCTATATGGTTTGATGCGTACGACAAATACT
CAGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCAC ATGCAGACGCCGTGAAGGGCCGATTCACCATCTCCA
NA
TCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGC GAGACAACTCCAAGAACACGCTGTATCTGCAAATG
AGTTTATTACTGTCAGCAGTATAACAACTGGCCTCT AACAGCCTGAGAGCCGAGGACACGGCTGTGTATTA
00
n
in CACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
CTGTGCGAGAGATAAGTCGATTTTTGGAGTGGTCCC 1-3
.7r
n
CGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTC
cp
o n.)
PI TAGT
(SEQ ID NO: 949) (SEQ ID NO: 950)
o
oe
'a
oe
cA
oe
74
A-2164-WO-PCT
EIVMTQ SP ATL SV SP GERATL SCRASQ SVNRHLAWYQ QVQLVESGGGVVQPGRSLRL
SCAASGFTFQNYGMHW
QKP GQAPRLLIYEAATRATGIPARF S GS GS GTEFTLTI S VRQAP GE GLEWVAAIWFD
AYDKYYADAVKGRFTI SR
AA SLQSEDFAVYYCQQYNNWPLTFGGGTKVEIK
DNSKNTLYLQMNSLRAEDTAVYYCARDKSIFGVVPD 0
YWGQGTLVTVSS
n.)
o
(SEQ ID NO: 951) (SEQ ID NO: 952)
oe
i-J
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGT
c,.)
--.1
GTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGG CCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGC
o
--.1
GCCAGTCAGAGTGTTACCAGCCACTTAGCCTGGTAC ATCTGGATTCACCTTCCAGAACTATGGCATGCACTG
CAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATC GGTCCGCCAGGCTCCAGGCGAGGGGCTGGAGTGGG
TACGAAGCAGCCACCAGGGCCACTGGTATCCCAGC TGGCAGCTATATGGTTTGATGCGTACGACAAATACT
CAGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCAC ATGCAGACGCCGTGAAGGGCCGATTCACCATCTCCA
NA
TCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGC GAGACAACTCCAAGAACACGCTGTATCTGCAAATG
AGTTTATTACTGTCAGCAGTATAACCAGTGGCCTCT AACAGCCTGAGAGCCGAGGACACGGCTGTGTATTA
CACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA CTGTGCGAGAGATCTCGCGATTTTTGGAGTGGTCCC
CGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTC
TAGT
p
(SEQ ID NO: 953) (SEQ ID NO: 954)
.
L.
EIVMTQ SP ATL SV SP GERATL SCRASQ SVT SHLAWYQ QVQLVESGGGVVQPGRSLRL
SCAASGFTFQNYGMHW "
,
in QKP GQAPRLLIYEAATRATGIPARF S GS GS GTEFTLTI S VRQAP GE GLEWVAAIWFD
AYDKYYADAVKGRFTI SR .
f el o AA SLQSEDFAVYYCQQYNQWPLTFGGGTKVEIK
DNSKNTLYLQMNSLRAEDTAVYYCARDLAIFGVVPD
PI YWGQGTLVTVSS
(SEQ ID NO: 955) (SEQ ID NO: 956)
,
L.
,
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGT
GTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGG CCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGC
GCCAGTCAGAGTGTTGATCAGCACTTAGCCTGGTAC ATCTGGATTCACCTTCCAGAACTATGGCATGCACTG
CAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATC GGTCCGCCAGGCTCCAGGCGAGGGGCTGGAGTGGG
TACCAGGCAGCCACCAGGGCCACTGGTATCCCAGCC TGGCAGCTATATGGTTTGATGCGGCTTTCAAATACT
AGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCACT ATGCAGACGCCGTGAAGGGCCGATTCACCATCTCCA
NA
CTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGCA GAGACAACTCCAAGAACACGCTGTATCTGCAAATG
GTTTATTACTGTCAGCAGTATCAGAACTGGCCTCTC AACAGCCTGAGAGCCGAGGACACGGCTGTGTATTA
00
n
o
ACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
CTGTGCGAGAGATCTCGCGATTTTTGGAGTGGTCCC 1-3
f e)
f el
CGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTC
cp
o n.)
PI TAGT
(SEQ ID NO: 957) (SEQ ID NO: 958)
o
oe
'a
oe
cA
oe
A-2164-WO-PCT
EIVMTQSPATLSVSPGERATLSCRASQSVDQHLAWYQ QVQLVESGGGVVQPGRSLRLSCAASGFTFQNYGMHW
QKPGQAPRLLIYQAATRATGIPARFSGSGSGTEFTLTIS VRQAPGEGLEWVAAIWFDAAFKYYADAVKGRFTISR
AA SLQSEDFAVYYCQQYQNWPLTFGGGTKVEIK
DNSKNTLYLQMNSLRAEDTAVYYCARDLAIFGVVPD 0
YWGQGTLVTVSS
n.)
o
(SEQ ID NO: 959) (SEQ ID NO: 960)
oe
i-J
ATGGACATGAGGGTGCCCGCTCAGCTCCTGGGGCTC ATGGACATGAGGGTGCCCGCTCAGCTCCTGGGGCTC
c,.)
--.1
CTGCTGCTGTGGCTGAGAGGTGCGCGCTGTGAAATC CTGCTGCTGTGGCTGAGAGGTGCGCGCTGTCAGGTG
o
--.1
GTGATGACGCAGTCTCCAGCCACCCTGTCTGTGTCT CAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCC
CCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAG TGGGAGGTCCCTGAGACTCTCCTGTGCAGCATCTGG
TCAGAGTGTTAGCGAACACTTAGCCTGGTACCAGCA ATTCACCTTCAGTAACTATGGCATGCACTGGGTCCG
GAAACCTGGCCAGGCTCCCAGGCTCCTCATCTACGA CCAGGCTCCAGGCGAGGGGCTGGAGTGGGTGGCAG
NA
,- AGCAGCCACCAGGGCCACTGGTATCCCAGCCAGGTT
CTATCTGGTTTGATGCAAGTGATAAATACTATGCAG
oe
re) CAGTGGCAGTGGGTCTGGGACAGAGTTCACTCTCAC
ACGCCGTGAAGGGCCGATTCACCATCTCCAGAGAC
o,
" CATCAGCAGCCTGCAGTCTGAAGATTTTGCAGTT AACTCCAAGAACACGCTGTATCTGCAAATGAACAG
in
ci3
CCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGC
0.0
¨ GAGA
p
(SEQ ID NO: 1377 (SEQ ID NO: 1378
.
L.
EIVMTQSPATLSVSPGERATLSCRASQSVSEHLAWYQ QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMHW
.
,
QKPGQAPRLLIYEAATRATGIPARFSGSGSGTEFTLTIS VRQAPGEGLEWVAAIWFDASDKYYADAVKGRFTISR
.
AA SLQSEDFAVYYCQQYQNWPLTFGGGTKVEIK
DNSKNTLYLQMNSLRAEDTAVYYCARDLAIFGVIPDY o
,
WGQGTLVTVSS
,
(SEQ ID NO: 1086) (SEQ ID NO: 1287)
'
L.
,
ATGGACATGAGGGTGCCCGCTCAGCTCCTGGGGCTC ATGGACATGAGGGTGCCCGCTCAGCTCCTGGGGCTC
CTGCTGCTGTGGCTGAGAGGTGCGCGCTGTGAAATC CTGCTGCTGTGGCTGAGAGGTGCGCGCTGTCAGGTG
GTGATGACGCAGTCTCCAGCCACCCTGTCTGTGTCT CAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCC
CCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAG TGGGAGGTCCCTGAGACTCTCCTGTGCAGCATCTGG
TCAGAGTGTTAGCAGCAACTTAGCCTGGTACCAGCA ATTCACCTTCAGTAACTATGGCATGCACTGGGTCCG
c-1
oe A GAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGG CCAGGCTCCAGGCGAGGGGCTGGAGTGGGTGGCAG
rn N
o, TGCAGCCACCAGGGCCACTGGTATCCCAGCCAGGTT
CTATCTGGTTTGATGCAAGTGATAAATACTATGCAG
"
in CAGTGGCAGTGGGTCTGGGACAGAGTTCACTCTCAC
ACGCCGTGAAGGGCCGATTCACCATCTCCAGAGAC oo
cz
n
0.0 CATCAGCAGCCTGCAGTCTGAAGATTTTGCAGTT AACTCCAAGAACACGCTGTATCTGCAAATGAACAG
1-3
¨
CCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGC
cp
GAGA
n.)
o
(SEQ ID NO: 1379 (SEQ ID NO: 1380
oe
'a
AA
EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQ QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMHW
w
oe
KPGQAPRLLIYGAATRATGIPARFSGSGSGTEFTLTISS VRQAPGEGLEWVAAIWFDASDKYYADAVKGRFTISR
cA
oe
76
A-2164-WO-PCT
LQSEDFAVYYCQQYNNWPLTFGGGTKVEIK
DNSKNTLYLQMNSLRAEDTAVYYCARDIAIFGVVPDY
WGQGTLVTVSS
(SEQ ID NO: 1296) (SEQ ID NO: 1297)
0
n.)
ATGGACATGAGGGTGCCCGCTCAGCTCCTGGGGCTC ATGGACATGAGGGTGCCCGCTCAGCTCCTGGGGCTC
=
CTGCTGCTGTGGCTGAGAGGTGCGCGCTGTGAAATC CTGCTGCTGTGGCTGAGAGGTGCGCGCTGTCAGGTG
oe
i-J
GTGCTGACGCAGTCTCCAGCCACCCTGTCTCTGTCT CAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCC
c,.)
--.1
CCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAG TGGGAGGTCCCTGAGACTCTCCTGTGCAGCATCTGG
o
o
--.1
TCAGAGTGTTAGCAGCAACTTAGCCTGGTACCAGCA ATTCACCTTCAGTAACTATGGCATGCACTGGGTCCG
NA GAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGG CCAGGCTCCAGGCGAGGGGCTGGAGTGGGTGGCAG
N TGCAGCCACCAGGGCCACTGGTATCCCAGACAGGTT
CTATCTGGTTTGATGCAAGTGATAAATACTATGCAG
o
rn CAGTGGCAGTGGGTCTGGGACAGAGTTCACTCTCAC
ACGCCGTGAAGGGCCGATTCACCATCTCCAGAGAC
o
r'l CATCAGCAGGCTGGAGCCTGAAGATTTTGCAGTT AACTCCAAGAACACGCTGTATCTGCAAATGAACAG
in
ci3
CCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGC
0.0
¨ GAGA
(SEQ ID NO: 1381 (SEQ ID NO: 1382
EIVLTQSPATLSLSPGERATLSCRASQSVSSNLAWYQQ QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMHW
p
AA KPGQAPRLLIYGAATRATGIPDRFSGSGSGTEFTLTISR
VRQAPGEGLEWVAAIWFDASDKYYADAVKGRFTISR .
L.
LEPEDFAVYYCQQYNNWPLTFGGGTKVEIK
DNSKNTLYLQMNSLRAEDTAVYYCARDQAIFGVVPD .
,
YWGQGTLVTVSS
.
(SEQ ID NO: 1306) (SEQ ID NO: 1307)
,
ATGGACATGAGGGTGCCCGCTCAGCTCCTGGGGCTC ATGGACATGAGGGTGCCCGCTCAGCTCCTGGGGCTC
,
CTGCTGCTGTGGCTGAGAGGTGCGCGCTGTGAAATC CTGCTGCTGTGGCTGAGAGGTGCGCGCTGTCAGGTG
'
L.
,
GTGCTGACGCAGTCTCCAGCCACCCTGTCTCTGTCT CAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCC
CCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAG TGGGAGGTCCCTGAGACTCTCCTGTGCAGCATCTGG
TCAGAGTGTTAGCGAACACTTAGCCTGGTACCAGCA ATTCACCTTCAGTAACTATGGCATGCACTGGGTCCG
GAAACCTGGCCAGGCTCCCAGGCTCCTCATCTACGA CCAGGCTCCAGGCGAGGGGCTGGAGTGGGTGGCAG
o NA
o AGCAGCCACCAGGGCCACTGGTATCCCAGACAGGT CTATCTGGTTTGATGCAAGTGATAAATACTATGCAG
re)
01 TCAGTGGCAGTGGGTCTGGGACAGAGTTCACTCTCA
ACGCCGTGAAGGGCCGATTCACCATCTCCAGAGAC
"
in CCATCAGCAGGCTGGAGCCTGAAGATTTTGCAGTT
AACTCCAAGAACACGCTGTATCTGCAAATGAACAG
ci3
0.0
CCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGC oo
-
n
GAGA
1-3
(SEQ ID NO: 1383 (SEQ ID NO: 1384
cp
EIVLTQSPATLSLSPGERATLSCRASQSVSEHLAWYQQ QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMHW
n.)
o
AA
KPGQAPRLLIYEAATRATGIPDRFSGSGSGTEFTLTISR VRQAPGEGLEWVAAIWFDASDKYYADAVKGRFTISR
oe
'a
LEPEDFAVYYCQQYQNWPLTFGGGTKVEIK
DNSKNTLYLQMNSLRAEDTAVYYCARDLAIFGVIPDY c,.)
oe
WGQGTLVTVSS
o
oe
77
A-2164-WO-PCT
(SEQ ID NO: 1316) (SEQ ID NO: 1317)
ATGGACATGAGGGTGCCCGCTCAGCTCCTGGGGCTC ATGGACATGAGGGTGCCCGCTCAGCTCCTGGGGCTC
CTGCTGCTGTGGCTGAGAGGTGCGCGCTGTGAAATC CTGCTGCTGTGGCTGAGAGGTGCGCGCTGTCAGGTG
0
n.)
GTGCTGACGCAGTCTCCAGCCACCCTGTCTCTGTCT CAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCC
=
CCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAG TGGGAGGTCCCTGAGACTCTCCTGTGCAGCATCTGG
oe
i-J
TCAGAGTGTTAGCAGCAACTTAGCCTGGTACCAGCA ATTCACCTTCAGTAACTATGGCATGCACTGGGTCCG
c,.)
--.1
GAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGG CCAGGCTCCAGGCGAGGGGCTGGAGTGGGTGGCAG
o
o
NA
--.1
o TGCAGCCACCAGGGCCACTGGTATCCCAGACAGGTT CTATCTGGTTTGATGCAAGTGATAAATACTATGCAG
o
.7r CAGTGGCAGTGGGTCTGGGACAGAGTTCACTCTCAC
ACGCCGTGAAGGGCCGATTCACCATCTCCAGAGAC
o
e'l CATCAGCAGGCTGGAGCCTGAAGATTTTGCAGTT AACTCCAAGAACACGCTGTATCTGCAAATGAACAG
in
ci3
CCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGC
0.0
¨ GAGA
(SEQ ID NO: 1385 (SEQ ID NO: 1386
EIVLTQSPATLSLSPGERATLSCRASQSVSSNLAWYQQ QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMHW
KPGQAPRLLIYGAATRATGIPDRFSGSGSGTEFTLTISR VRQAPGEGLEWVAAIWFDASDKYYADAVKGRFTISR
AA LEPEDFAVYYCQQYNNWPLTFGGGTKVEIK
DNSKNTLYLQMNSLRAEDTAVYYCARDIAIFGVVPDY p
WGQGTLVTVSS
(SEQ ID NO: 1326) (SEQ ID NO: 1327)
.
,
ATGGACATGAGGGTGCCCGCTCAGCTCCTGGGGCTC ATGGACATGAGGGTGCCCGCTCAGCTCCTGGGGCTC
.
CTGCTGCTGTGGCTGAGAGGTGCGCGCTGTGAAATC CTGCTGCTGTGGCTGAGAGGTGCGCGCTGTCAGGTG
o
,
GTGCTGACGCAGTCTCCAGCCACCCTGTCTCTGTCT CAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCC
.
,
,
CCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAG TGGGAGGTCCCTGAGACTCTCCTGTGCAGCATCTGG
'
L.
,
TCAGAGTGTTGATCTGCACTTAGCCTGGTACCAGCA ATTCACCTTCAGTAACTATGGCATGCACTGGGTCCG
GAAACCTGGCCAGGCTCCCAGGCTCCTCATCTACGA CCAGGCTCCAGGCGAGGGGCTGGAGTGGGTGGCAG
NA
f9) AGCAGCCACCAGGGCCACTGGTATCCCAGACAGGT
CTATCTGGTTTGATGCAAGTGATAAATACTATGCAG
o
.7r TCAGTGGCAGTGGGTCTGGGACAGAGTTCACTCTCA
ACGCCGTGAAGGGCCGATTCACCATCTCCAGAGAC
ff)
01
r,1 CCATCAGCAGGCTGGAGCCTGAAGATTTTGCAGTT
AACTCCAAGAACACGCTGTATCTGCAAATGAACAG
in
ci3
CCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGC
0.0 GAGA
¨
(SEQ ID NO: 1387 (SEQ ID NO: 1388
00
n
EIVLTQSPATLSLSPGERATLSCRASQSVDLHLAWYQQ QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMHW
1-3
KPGQAPRLLIYEAATRATGIPDRFSGSGSGTEFTLTISR VRQAPGEGLEWVAAIWFDASDKYYADAVKGRFTISR
cp
AA LEPEDFAVYYCQQYQNWPLTFGGGTKVEIK
DNSKNTLYLQMNSLRAEDTAVYYCARDLAIFGVVPD n.)
o
YWGQGTLVTVSS
oe
'a
(SEQ ID NO: 1336) (SEQ ID NO: 1337)
c,.)
oe
4 NA ATGGACATGAGGGTGCCCGCTCAGCTCCTGGGGCTC ATGGACATGAGGGTGCCCGCTCAGCTCCTGGGGCTC
o
oe
78
A-2164-WO-PCT
CTGCTGCTGTGGCTGAGAGGTGCGCGCTGTGAAATC CTGCTGCTGTGGCTGAGAGGTGCGCGCTGTCAGGTG
GTGCTGACGCAGTCTCCAGCCACCCTGTCTCTGTCT CAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCC
CCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAG TGGGAGGTCCCTGAGACTCTCCTGTGCAGCATCTGG
0
n.)
TCAGAGTGTTAACCTGAACTTAGCCTGGTACCAGCA ATTCACCTTCAGTAACTATGGCATGCACTGGGTCCG
o
GAAACCTGGCCAGGCTCCCAGGCTCCTCATCTACCA CCAGGCTCCAGGCGAGGGGCTGGAGTGGGTGGCAG
oe
i-J
GGCAGCCACCAGGGCCACTGGTATCCCAGACAGGT CTATCTGGTTTGATGCAAGTGATAAATACTATGCAG
c,.)
--.1
TCAGTGGCAGTGGGTCTGGGACAGAGTTCACTCTCA ACGCCGTGAAGGGCCGATTCACCATCTCCAGAGAC
o
o
CCATCAGCAGGCTGGAGCCTGAAGATTTTGCAGTT AACTCCAAGAACACGCTGTATCTGCAAATGAACAG
--.1
CCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGC
GAGA
(SEQ ID NO: 1389 (SEQ ID NO: 1390
EIVLTQ SP ATL SL SP GERATL SCRASQ SVNLNLAWYQQ QVQLVE SGGGVVQPGRSLRL
SCAASGFTFSNYGMHW
KPGQAPRLLIYQAATRATGIPDRFSGSGSGTEFTLTISR VRQAPGEGLEWVAAIWFDASDKYYADAVKGRFTISR
AA LEPEDFAVYYCQQYNQWPLTFGGGTKVEIK
DNSKNTLYLQMNSLRAEDTAVYYCARDLAIFGVVPD
YWGQGTLVTVSS
(SEQ ID NO: 1346) (SEQ ID NO: 1347)
p
ATGGACATGAGGGTGCCCGCTCAGCTCCTGGGGCTC ATGGACATGAGGGTGCCCGCTCAGCTCCTGGGGCTC
.
L.
CTGCTGCTGTGGCTGAGAGGTGCGCGCTGTGAAATC CTGCTGCTGTGGCTGAGAGGTGCGCGCTGTCAGGTG
.
,
GTGCTGACGCAGTCTCCAGCCACCCTGTCTCTGTCT CAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCC
.
CCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAG TGGGAGGTCCCTGAGACTCTCCTGTGCAGCATCTGG
,
TCAGAGTGTTTTCAGCCACTTAGCCTGGTACCAGCA ATTCACCTTCCAGAACTATGGCATGCACTGGGTCCG
.
,
,
GAAACCTGGCCAGGCTCCCAGGCTCCTCATCTACGA CCAGGCTCCAGGCGAGGGGCTGGAGTGGGTGGCAG
.
,
NA
L.
,
in AGCAGCCACCAGGGCCACTGGTATCCCAGACAGGT
CTATCTGGTTTGATGCGTCTGACAAATACTATGCAG
o
.7r TCAGTGGCAGTGGGTCTGGGACAGAGTTCACTCTCA
ACGCCGTGAAGGGCCGATTCACCATCTCCAGAGAC
o
r'l CCATCAGCAGGCTGGAGCCTGAAGATTTTGCAGTT
AACTCCAAGAACACGCTGTATCTGCAAATGAACAG
in
ci3
CCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGC
0.0
¨ GAGA
(SEQ ID NO: 1391 (SEQ ID NO: 1392
EIVLTQ SP ATL SL SP GERATL SCRAS Q SVF SHLAWYQQ QVQLVESGGGVVQPGRSLRL
SCAASGFTFQNYGMHW
KPGQAPRLLIYEAATRATGIPDRFSGSGSGTEFTLTISR VRQAPGEGLEWVAAIWFDASDKYYADAVKGRFTISR
00
n
AA LEPEDFAVYYCQQYQNWPLTFGGGTKVEIK
DNSKNTLYLQMNSLRAEDTAVYYCARDLAIFGVVPD 1-3
YWGQGTLVTVSS
cp
(SEQ ID NO: 1356) (SEQ ID NO: 1357)
n.)
o
oe
'a
oe
cA
oe
79
A-2164-WO-PCT
Table 4. Exemplary CDRL1, CDRL2, CDRL3, CDRH1, CDRH2, and CDRH3 Nucleic Acid
("NA") and Amino Acid ("AA") Sequences
0
w
Table 4A. Exemplary CDRL1, CDRL2, and CDRL3 Nucleic Acid ('NA") and Amino Acid
("AA") Sequences o
1-,
oe
i-J
W
=TylWomoniiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiCpnriiiiiiiiiiiiiiiiiiiiiiiiiii
iiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiii
iiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiicowiii
ii!i!i!i!i!i!i!i!i!i!Mg2Qommini!i!i!i!i!i!i!i!i!i!i!i!i!i!i!i!i!iiicOn3iniiiiii
iiiiiiiiiiiiiiiiiiiimmga -4
=
AGGGCCAGTCAGAGTGTTGATAG GAAGCAGCCACCAGGGCCACT .CAGCAGTATCAGAACTGGCCTCT
o
-4
rn NA ACACTTAGCC CACT
o
,P1 (SEQ ID NO: 1) (SEQ ID NO: 2) (SEQ ID
NO: 3)
o
RASQSVDRHLA EAATRAT QQYQNWPLT
(SEQ ID NO: 4) (SEQ ID NO: 5) (SEQ ID
NO: 6)
AGGGCCAGTCAGAGTGTTAACAG GAAGCAGCCACCAGGGCCACT CAGCAGTATCAGAACTGGCCTCT
71. NA ACACTTAGCC CACT
o
,P1 (SEQ ID NO: 7) (SEQ ID NO: 8) (SEQ ID
NO: 9)
o P
RASQSVNRHLA EAATRAT QQYQNWPLT
(SEQ ID NO: 10) (SEQ ID NO: 11) (SEQ ID
NO: 12) .
AGGGCCAGTCAGAGTGTTCATAG GAAGCAGCCACCAGGGCCACT CAGCAGTATCAGAACTGGCCTCT
,
rn NA ACACTTAGCC CACT
c,
(-1
,
ri (SEQ ID NO: 13) (SEQ ID NO: 14) (SEQ ID
NO: 15) ' ,
o ,
RASQSVHRHLA EAATRAT QQYQNWPLT
c,
,
,
(SEQ ID NO: 16) (SEQ ID NO: 17) (SEQ ID
NO: 18)
AGGGCCAGTCAGAGTGTTGAAAG GAAGCAGCCACCAGGGCCACT CAGCAGTATCAGAACTGGCCTCT
o NA
ACACTTAGCC CACT
o
,P1 (SEQ ID NO: 19) (SEQ ID NO: 20) (SEQ ID
NO: 21)
o
RASQSVERHLA EAATRAT QQYQNWPLT
c:ji AA
(SEQ ID NO: 22) (SEQ ID NO: 23) (SEQ ID
NO: 24)
AGGGCCAGTCAGAGTGTTTTCAG GAAGCAGCCACCAGGGCCACT CAGCAGTATCAGAACTGGCCTCT
1-d
NA ACACTTAGCC CACT
n
,-i
,-,
,P1 (SEQ ID NO: 25) (SEQ ID NO: 26) (SEQ ID
NO: 27)
o cp
RASQSVFRHLA EAATRAT QQYQNWPLT
w
o
(SEQ ID NO: 28) (SEQ ID NO: 29) (SEQ ID
NO: 30) oe
'a
oe
o
oe
18
oo
(.9)
x r, IWO
339VII3VaD
o VN
oo
IDIDOODIOVVDVDIVIDVaDVD IDVDaDODVDDVDaDVaDVVD
DVDIaLIDIDVDVDIDVDaDODV
,-
= (99 :ON CH OHS)
(S9 :ON CH OHS) (179 :ON CH OHS)
el
VV
ci)
rIcIMNOAO0 IVIIIVVH VIHSINASOSVII
P
(E9 :ON CH OHS) (Z9 :ON CH OHS) (19 :ON CH OHS)
c,.)
Pi IWO
3aDVII3V3L VN w
IDIDOODIOVVDVDIVIDVaDVD IDVDaDODVDDVDaDVaDVVD DVDIVIIDIDVDVDIDVDaDODV
(09 :ON CH OHS) (6g :ON CH OHS) (8S :cm m Os)
rIcIMNOAO0 IVIIIVVH VIHSIASOSVII o
(LS :ON CFI OHS) (9g :ON CH OHS) (SS :cm m Os) 44
k.)
IWO DaDVII3VaL
VN 4==
IDIDOODIOVVDVDIVIDVaDVD IDVDaDODVDDVDaDVaDVVD DVDIaLIDIDVDVDIDVDaDODV
,
(17g :ON CFI OHS) (Eg :ON CFI OHS) (ZS :ON m Os) ,
. vv ''
,
,
rIcIANNAO0 IVIIIVVH VIHSIASOSVII
, o
'
QS :ON CFI OHS) (Og :ON CFI OHS) (617 :ON CEI OHS) 44
.:,
IWO DaDVII3VaL
VN oe
,
' .
IDIDOODIOVVOVVIVIDVaDVD IDVDaDODVDDVDaDVaDVVD
DVDIaLIDIDVDVDIDVDaDODV
o
(817 :ON CFI OHS) (L17 :ON CFI OHS) (917 :ON CH OHS)
6
VV
rIcIMNOAO0 IVIIIVVH VIHIMASOSVII
P
(St :ON CFI OHS) (1717 :ON CFI OHS) (Et :ON m Os)
c:
IWO 33-DVII3V3V
VN w
IDIDOODIOVVDVDIVIDVaDVD IDVDaDODVDDVDaDVaDVVD OVIVOLLDIDVDVDIDVDaDODV
(Z17 :ON CFI OHS) (117 :ON CFI OHS) (017 :ON m Os)
rIcIMNOAO0 IVIIIVVH VII-IIIHASOSVII
P
(6E :ON CH OHS) (8E :ON CFI OHS) (LE :ON m Os)
c:
N IWO
33-DVII3V3V VN
o,
o
N
IDIDOODIOVVDVDIVIDVaDVD IDVDaDODVDDVDaDVaDVVD
OVVVOLLDIDVDVDIDVDaDODV
(.9)
el (9E :ON CH OHS)
(SE :ON CFI OHS) (17E :cm m Os)
oe
vv ''
,. rIcIMNOAO0
IVIIIVVH VIHIINASOSVII
o
el
o
0 (EE :ON CFI OHS)
(ZE :ON CFI OHS) (I E :ON m Os) =c,,,
c:
IWO 339VII3V3V VN 4
IDIDOODIOVVDVDIVIDVaDVD IDVDaDODVDDVDaDVaDVVD OVOVVIIDIDVDVDIDVDaDODV
13d-OM-179T Z-V
Z8
oo
(.9)
oe rIcIMNOAO0
IVIIIVVH VIHSAASOSVII VV r.)
o
oo (SOT :ON CFI OHS)
(170I :ON CFI OHS) (E0I :ON m OHs) Z),
=
el IWO
DaDVIIDVDD VN o,
o
ci)
IDIDOODIOVVDVDIVIDVaDVD IDVDaDODVDDVDaDVaDVVD 9V3LLLL9I9V9V3L9V3aD99V
E*- (ZOI :ON CFI OHS)
(TOT :ON CFI OHS) (00i :ON m OHs)
Pi rIcIMNOAO0
IVIIIVVH VIHSAASOSVII
P
(66 :ON CH OHS) (86 :ON CH OHS) (L6 :ON (II OHS) c,.)
o
IWO DaDVIIDVDD
VN '
IDIDOODIOVVDVDIVIDVaDVD IDVDaDODVDDVDaDVaDVVD 9V3LLLL9I9V9V3L9V3aD99V
(II :ON CFI OHS) (g6 :ON CH OHS) (176 :ON CH OHS) VV k6
rIdMI-10A00 IVIIIVVH VII-IIISASOSVII
P
(E6 :ON CH OHS) (Z6 :ON CH OHS) (16 :ON CH OHS) c,.)
, IWO
33-DVLIDVD-D VN w
,
,
IaLDaDDIDVaDVDIVIDVaDVD I3VDaD99V33V3aDVaDVV9 93aDVII9I9V9V319V3aD99V
,
(06 :ON CH OHS) (68 :ON CH OHS) (88 :ON m Os)
1JdA1NOAO0 IVIIIVVH VII-IHSASOSVII
,
' . (L8 :ON CFI OHS)
(98 :ON CH OHS) (g8 :om m Os) L
k.)
o IWO 339V1I3V3V VN
IDIDOODIOVV-DVDIVIDVaDVD I3VDaD99V33V3aDVaDVV9 V9aDVII9I9V9V319V3aD99V
(78 :ON CFI OHS) (8 :ON CFI OHS) (Z8 :om m Os)
1JdA1NOAO0 IVIIIVVH VII-IHSASOSVII
P
(I8 :ON CFI OHS) (08 :ON CFI OHS) (6L :ON CH OHS) c,.)
r.)
IWO 33-DVLI3V3V
VN =
IDIDOODIOVV-DVDIVIDVaDVD I3VDaD99V33V3aDVaDVV9 V9aDVII9I9V9V319V3aD99V
(8L :ON CFI OHS) (LL :ON CFI OHS) (9L :ON CH OHS) VV k6
N 1JdA1NOAO0
IVIIIVVH VIITICEASOSVII
o,
P
t--= (SL :ON CFI OHS)
(17L :ON CFI OHS) (EL :ON m Os) w
" IWO
33-DV1I3VD-D VN '
oo
,-
IDIDOODIOVV-DVDIVIDVaDVD I3V30099V33V300VaDVV9
I3IVOLLDIDV9V3LDV30099V
o
el
0 (ZL :ON CFI OHS)
(IL :ON CFI OHS) (OL :om m Os)
vv
1JdA1NOAO0 IVIIIVVH VII-IrIASOSVII
(69 :ON CH OHS) (89 :ON CH OHS) (L9 :ON CH OHS)
13d-0M-179T Z-V
8
oo
(.9)
oo
(.9)
o
oo (17171 :ON CFI WS)
(EtT :ON CFI OHS) (Z171 :ON m Os)
,.
VV kt4
= rIcIANNAO0
IVITIVVH VIHIAASOSVIT
el
5:
ci)
(ItT :ON CFI WS) (0171 :ON CFI OHS) (6E1 :ON CH OHS)
c,.)
E*- IWO
33-DVII3VaD VN c:
c.)
Pi
IDIDOODIOVVOVVIVIDVaDVD I3VDaD99V33V3aDVaDVV9
OVOILLIDIDVDVaLDVDaDODV
(SET :ON CFI WS) (LET :ON CFI OHS) (9ET :ON CH
OHS) VV k6
rIcIMOOAO0 IVITIVVH VII-ISSASOSVIT
5:
(SET :ON CFI WS) (17T :ON CFI OHS) (EET :ON m Os)
c,.)
4==
IWO DaDVIIDVDD
VN 4.
IDIDOODIDVaDVDIVIDVaDVD I3VDaD99V33V3aDVaDVV9 9VI9VII9I9V9V3L9V3aD99V
(ZET :ON CFI OHS) 0E1 :ON CFI OHS) WET :ON m OHs)
, vv ''
, ridAVNIOAO0
IVITIVVH VIHSOASOSVIT
. o
,
,
(6ZI :ON CH WS) (SZT :ON CFI OHS) (LZT :ON m Os)
44
,
IWO DaDVIIDVDD VN
.:,
IDIDOODIOVV-DVDIVIDVaDVD I3VDaD99V33V3aDVaDVV9 9V9V3LL9I9V9V3L9V3aD99V
,
' . (9ZT :ON CH WS)
(SZT :ON CFI OHS) (17ZI :ON m Os)
vv ''
rIcIMOOAO0 IVITIVVH VIHSAASOSVIT
0
5:
(EZT :ON CFI OHS) (ZZI :ON CFI OHS) (I Z1 :ON m OHs)
c:
IWO DaDVIIDVDD
VN oe
IDIDOODIDVaDVDIVIDVaDVD I3VDaD99V33V3aDVaDVV9 OVOILLIDIDVDVaLDVDaDODV
(OZT :ON CFI OHS) (611 :ON CEI OHS) (SIT :ON m
OHs) VV kt4
rIcIMOOAO0 IVITIVVH VIHSAASOSVIT
5:
(LIT :ON CFI OHS) (911 :ON CEI OHS) (SIT :ON m OHs)
c,.)
c:
IWO DaDVIIDVDD
VN co
N
IDIDOODIDVaDVDIVIDVaDVD I3VDaD99V33V3aDVaDVV9
OVOILLIDIDVDVaLDVDaDODV
o,
N= (17T 1 :ON CFI OHS)
(ET 1 :ON CFI OHS) (z1 1 :ON m OHs)
m
VV k6)
el rIcIMOOAO0
IVITIVVH VIHSIASOSVIT
oo
o
,- (I 1 1 :ON CFI OHS)
(OTT :ON CFI OHS) (60T :ON CEI OHS) 44
or.)
el
0 IWO
3aDVII3V3L VN
IDIDOODIDVaDVDIVIDVaDVD I3VDaD99V33V3aDVaDVV9 9V9I3LI9I9V9V3L9V3aD99V
(80T :ON CFI OHS) (LOT :ON CFI OHS) (901 :ON CEI OHS)
13d-OM-179T Z-V
A-2164-WO-PCT
AGGGCCAGTCAGAGTGTTTTCAC GAAGCAGCCACCAGGGCCACT CAGCAGTATAACAACTGGCCTCT
o NA
GCACTTAGCC CACT
`z. (SEQ ID NO: 145) (SEQ ID NO: 146) (SEQ ID
NO: 147)
o n.)
RASQSVFTHLA EAATRAT QQYNNWPLT
o
PI AA
oe
(SEQ ID NO: 148) (SEQ ID NO: 149) (SEQ ID
NO: 150) t''J
AGGGCCAGTCAGAGTGTTTTTGA GAAGCAGCCACCAGGGCCACT CAGCAGTATAACAACTGGCCTCT
--.1
o
(-,1 NA ACACTTAGCC CACT
--.1
,--i
ri (SEQ ID NO: 151) (SEQ ID NO: 152) (SEQ ID
NO: 153)
o
,-I RASQSVFEHLA EAATRAT QQYNNWPLT
(SEQ ID NO: 154) (SEQ ID NO: 155) (SEQ ID
NO: 156)
AGGGCCAGTCAGAGTGTTGAACA GAAGCAGCCACCAGGGCCACT CAGCAGTATAACAACTGGCCTCT
cr NA GCACTTAGCC CACT
ri (SEQ ID NO: 157) (SEQ ID NO: 158) (SEQ ID
NO: 159)
o
RASQSVEQHLA EAATRAT QQYNNWPLT
PI AA
P
(SEQ ID NO: 160) (SEQ ID NO: 161) (SEQ ID
NO: 162) .
L.
AGGGCCAGTCAGAGTGTTCATAG GAAGCAGCCACCAGGGCCACT CAGCAGTATAACCAGTGGCCTCT
.
N NA CCACTTAGCC CACT
,
(.91 (SEQ ID NO: 163) (SEQ ID NO: 164) (SEQ ID
NO: 165) " o ,
RASQSVHSHLA EAATRAT QQYNQWPLT
.
,
PI AA
,
' (SEQ ID NO: 166) (SEQ ID
NO: 167) (SEQ ID NO: 168) L.
,
AGGGCCAGTCAGAGTGTTCATCA GAAGCAGCCACCAGGGCCACT CAGCAGTATAACCAGTGGCCTCT
oe NA TCACTTAGCC CACT
rn
n (SEQ ID NO: 169) (SEQ ID NO: 170) (SEQ ID
NO: 171)
o
RASQSVHHHLA EAATRAT QQYNQWPLT
PI AA
(SEQ ID NO: 172) (SEQ ID NO: 173) (SEQ ID
NO: 174)
AGGGCCAGTCAGAGTGTTCATAG GAAGCAGCCACCAGGGCCACT CAGCAGTATAACAACTGGCCTCT
7r NA CCACTTAGCC CACT
00
,-,
n
ri (SEQ ID NO: 175) (SEQ ID NO: 176) (SEQ ID
NO: 177) 1-3
o
RASQSVHSHLA EAATRAT QQYNNWPLT
PI AA
cp
n.)
(SEQ ID NO: 178) (SEQ ID NO: 179) (SEQ ID
NO: 180) =
AGGGCCAGTCAGAGTGTTGATGT GAAGCAGCCACCAGGGCCACT CAGCAGTATAACCAGTGGCCTCT
oe
C., NA
CAACTTAGCC CACT
'a
oe
cA
oe
84
A-2164-WO-PCT
(SEQ ID NO: 181) (SEQ ID NO: 182) (SEQ ID
NO: 183)
RASQSVDVNLA EAATRAT QQYNQWPLT
AA
0
(SEQ ID NO: 184) (SEQ ID NO: 185) (SEQ ID
NO: 186) n.)
AGGGCCAGTCAGAGTGTTGATGT GAAGCAGCCACCAGGGCCACT CAGCAGTATAACCAGTGGCCTCT
o
1-,
oe
,--1 NA CCACTTAGCC CACT
t''J
ri (SEQ ID NO: 187) (SEQ ID NO: 188) (SEQ ID
NO: 189) -4
o
o v:,
,-I RASQSVDVHLA EAATRAT QQYNQWPLT
-4
(SEQ ID NO: 190) (SEQ ID NO: 191) (SEQ ID
NO: 192)
AGGGCCAGTCAGAGTGTTTTTGA GAAGCAGCCACCAGGGCCACT CAGCAGTATAACAACTGGCCTCT
NA ACACTTAGCC CACT
o
ri (SEQ ID NO: 193) (SEQ ID NO: 194) (SEQ ID
NO: 195)
o
,-I RASQSVFEHLA EAATRAT QQYNNWPLT
(SEQ ID NO: 196) (SEQ ID NO: 197) (SEQ ID
NO: 198)
AGGGCCAGTCAGAGTGTTTTTGA GAAGCAGCCACCAGGGCCACT CAGCAGTATAACAACTGGCCTCT
NA ACACTTAGCC CACT
P
`z. (SEQ ID NO: 199) (SEQ ID NO: 200) (SEQ ID
NO: 201) .
RASQSVFEHLA EAATRAT QQYNNWPLT
,
,0
PI AA
.
(SEQ ID NO: 202) (SEQ ID NO: 203) (SEQ ID
NO: 204)
,
AGGGCCAGTCAGAGTGTTTTCGA GAAGCAGCCACCAGGGCCACT CAGCAGTATAACCAGTGGCCTCT
.
,
,
in NA ACACTTAGCC CACT
,
ri (SEQ ID NO: 205) (SEQ ID NO: 206) (SEQ ID
NO: 207)
o
,-I RASQSVFEHLA EAATRAT QQYNQWPLT
(SEQ ID NO: 208) (SEQ ID NO: 209) (SEQ ID
NO: 210)
AGGGCCAGTCAGAGTGTTCTGGA GAAGCAGCCACCAGGGCCACT CAGCAGTATAACAACTGGCCTCT
rn NA ACACTTAGCC CACT
.7r
ri (SEQ ID NO: 211) (SEQ ID NO: 212) (SEQ ID
NO: 213)
o
,-I RASQSVLEHLA EAATRAT QQYNNWPLT
Iv
(SEQ ID NO: 214) (SEQ ID NO: 215) (SEQ ID
NO: 216) 1-3
rn AGGGCCAGTCAGAGTGTTGATAG GAAGCAGCCACCAGGGCCACT
CAGCAGTATAACCAGTGGCCTCT
cp
(T1 NA ACACTTAGCC CACT
o
o 1-,
(SEQ ID NO: 217) (SEQ ID NO: 218) (SEQ ID NO: 219)
oe
'a
" AA RASQSVDRHLA EAATRAT QQYNQWPLT
c,.)
oe
cr
oe
98
oo
(e)
oo
(e)
o
oo (8SZ :ON CFI WS)
(LSZ :ON CFI OHS) (9SZ :ON CH OHS)
,-
VV kt4
= IldANNAO0
IVITIVV9 VINSSASOSVII
el
P
ci)
(SSZ :ON CFI WS) (17SZ :ON CFI OHS) (ESZ :ON m Os)
c,.)
4==
E*- IWO
DODVII3VV3 VN
c.)
Pi
IDIDaDDIOVVIVVIVIDVaDVD IDVOYDDDVDDVOYDVaDIDD
DVaDVIIDIDVDVDIDVOYDODV
(ZSZ :ON CFI OHS) (I SZ :ON CFI OHS) (OSZ :ON m OHs)
ridANNA66 IvInvvo VINSSASOSVII
P
(617Z :ON CH WS) (817Z :ON CFI OHS) (L17Z :ON m Os)
c,.)
4==
IWO DODVII3VV3
VN --1
IDIDaDDIOVVIVVIVIDVaDVD IDVOYDDDVDDVOYDVaDIDD DVaDVIIDIDVDVDIDVOYDODV
(917Z :ON CH WS) (g17Z :ON CFI OHS) (1717Z :ON m Os)
, vv ''
, rIcIMNOAO0
IVIIIVVH VII-LLIASOSVII
. o
,
'
(El :ON (11 WS)
(Z17Z :ON (11 OHS) (I 17Z :ON aj Os)
=c,,,
, c:
IWO DODVIIDVDD
VN c`
.:,
IDIDOODIOVVDVDIVIDVaDVD I3VOYD99V33V3YDVaDVV9 DVDIaLIDIDVDVDIDVOYDODV
,
' . (017Z :ON CH WS)
(6EZ :ON CH OHS) (8EZ :ON m Os)
vv ''
rIcIMNOAO0 IVIIIVVH VII-LLIASOSVII
0
P
(LEZ :ON (11 WS) (9EZ :ON al OHS) (SEZ :ON m Os)
c,.)
c:
IWO DODVIIDVDD
VN c`
IDIDOODIOVVDVDIVIDVaDVD I3VOYD99V33V3YDVaDVV9 DVDIaLIDIDVDVDIDVOYDODV
(tEZ :ON (11 WS) (EEZ :ON (11 OHS) (ZEZ :ON aj
Os) VV kt4
IldMONAO0 IVITIVVO VIHANASOSVII
P
(TEZ :ON CFI OHS) (0EZ :ON CFI OHS) (6ZZ :ON (II OHS)
c,.)
IWO DODVIIDVDV VN
N
IDIDOODIDVDOVVIVIDVaDVD IDVOYDODVDDVOYDVaDDVD
IDOVVIIDIDVDVDIDVOYDODV
o
N= (8ZZ :ON CFI WS)
(LZZ :ON CFI OHS) (9ZZ :ON CH OHS)
el rIcIMOOAO0
IVIIIVVH VIHIINASOSVII
oo
o
,- (SZZ :ON CH WS)
(17ZZ :ON CH OHS) (EZZ :ON aj Os)
44
=
.
el
o
IWO DODVIIDVDD VN --1
IDIDOODIDVaDVDIVIDVaDVD I3VOYD99V33V3YDVaDVV9 DOOVVIIDIDVDVDIDVOYDODV
(ZZZ :ON CH WS) (I ZZ :ON CFI OHS) (OZZ :ON aj OHS)
13d-OM-179T Z-V
L8
oo
r.)
x r) IWO
DaDVIIOVVO
o VN
oo
IDIDOODIDVDOVVIVIOVaDVD IDVOYDOOVDDVDaDVaDOVO
IDOVVIIDIOVOVOIOVOYDOOV
,-
= (176Z :ON CH OHS)
(6Z :ON CH OHS) (Z6Z :ON CH OHS)
ci)
rldA1NOAO0 IVIIIVVN VINIHASOSVII P
(I6Z :ON CH OHS) (06Z :ON CH OHS) (68Z :ON CH OHS)
w
Pi IWO DaDVIIOVVO VN c:
IDIDOODIOVVOVOIVIOVaDVD IDVOYDOOVDDVDDOVaDOVV OVIVaLIDIOVOVOIOVOYDOOV
(88Z :ON m Os) (Lsz :cm m Os) (98z :cm CH OHS)
rldA1NOAO0 IVIIIVVN VINACEASOSVII o
(g8Z :ON m Os) (tsz :om m Os) (Esz :ON m Os)
=c,,,
c:
IWO 3DOVII3VVI VN
IDIDOODIOVVOVOIVIOVaDVD IDVOYDOOVDDVDDOVaDOVV IDIVOLLOIOVOVOIOVOYDOOV
,
(Z8Z :ON m Os) (I sz :om m Os)
(osz :om ajOHs) ,
. vv ''
,
,
ridAVNIOA66 IVIIIVVN VINACEASOSVII
, o
'
(6LZ :ON CH OHS) (8LZ :cm m Os) (LLz :cm m Os) 44
c:
IWO 3DOVII3VVI
VN 'A
,
' .
IDIDOODIOVVOVOIVIOVaDVD IDVOYDOOVDDVDDOVaDOVV
IDIVOLLOIOVOVOIOVOYDOOV
o
(9LZ :ON CH OHS) (SLZ :cm m Os) (i7Lz :cm m Os)
rIcIANNAO0 IVIIIVVH VINSSASOSVII P
(ELZ :cm m Os) (az :cm m Os) (iLz :cm m Os)
4=.
IWO ODOVII3VV3 VN
IDIDaDDIOVVIVVIVIOVaDVD IDVOYDOOVDDVDaDVaDVVO OVaDVIIDIOVOVOIOVOYDOOV
(OLZ :ON m Os) (69z :cm CH OHS) (89Z :ON CH
OHS) VV k6
rldANNAO0 IVIIIVV9 VINSSASOSVII P
(L9Z :ON CH WS) (99Z :ON CH OHS) (g9Z :ON CH OHS)
cl=
4=.
N IWO
ODOVII3VV3 VN --1
o
o
N
IDIDaDDIOVVIVVIVIOVaDVD IDVOYDOOVDDVDaDVaDIDO
OVaDVIIDIOVOVOIOVOYDOOV
r.)
el (I79Z :ON CH OHS)
(9Z :ON CH OHS) (Z9Z :ON CH OHS)
,- rldANNAO0
IVIIIVV9 VINSSASOSVII
o
el
o
0 (NZ :ON CH OHS)
(09Z :ON CH OHS) (6SZ :ON CH OHS) 44
4=.
IWO 339VII3VV3
VN c`
IDIDaDDIOVVIVVIVIOVaDVD IDVOYDOOVDDVDaDVaDIDO OVaDVIIDIOVOVOIOVOYDOOV
13d-OM-179T Z-V
88
oo
(.9)
(.9) rIcIMNOAO0
IVITIVVH VIT-TITAASOSVIT VV r.)
o
oo (EEE :ON CFI OHS)
(ZEE :ON CFI OHS) (TEE :ON m OHs) Z),
=
el IWO
33-DVLI3V3V VN c,.)
ci)
IDIDOODIOVV-DVDIVIDVaDVD I3VDaD99V33V3aDVaDVV9 OVOILLIDIDVDVaLDVDaDODV
(OEE :ON CFI WS) (6ZE :ON CH OHS) (8ZE :ON m Os)
Pi rIcIMOOAO0
IVITIVVH VIT-TITHASOSVIT
P
(LZE :ON CFI WS) (9ZE :ON CH OHS) (SZE :ON m Os) c,.)
4=.
IWO 33-DVLI3V3V
VN w
IDIDOODIDVaDVDIVIDVaDVD I3VDaD99V33V3aDVaDVV9 9VVV9LL9I9V9V3L9V3aD99V
(I7ZE :ON m Os) (EzE :ON m Os) (zzE :ON m Os)
rIcIMONAO0 IVITIVVH VIT-IIINASOSVIT
P
Oa :ON CFI OHS) (Oa :ON CFI OHS) (6T E :ON CH OHS) c,.)
,
r.)
, IWO
33-DVLIDVD-D VN '
,
,
IDIDaDDIDVDOVVIVIDVaDVD I3VDaD99V33V3aDVaDVV9 933VVII9I9V9V3L9V3aD99V
,
(8I E :ON CFI OHS) (LIE :ON CFI OHS) (9TE :ON CH OHS)
rIcIMONAO0 IVITIVVH VIT-IIICEASOSVIT
,
' . (SI E :ON CFI OHS)
(17T E :ON CFI OHS) (ET E :ON m OHs) *c.,
c:
0 IWO 339V1I3V3V VN --1
IDIDaDDIDVDOVVIVIDVaDVD I3VDaD99V33V3aDVaDVV9 9VIV9LL9I9V9V3L9V3aD99V
(ZI E :ON CFI OHS) (I I E :ON CFI OHS) (0 I E :ON m OHs)
rIcIMONAO0 IVITIVVH VIT-IIICEASOSVIT
P
(60 :ON CET WS) (80E :ON m Os) (LoE :ON m Os) c,.)
c:
IWO 33-DVLI3V3V
VN --1
IDIDaDDIDVDOVVIVIDVaDVD I3VDaD99V33V3aDVaDVV9 9VIV9LL9I9V9V3L9V3aD99V
(90E :ON CET WS) (SOE :ON m Os) (toE :ON m Os)
N riamONA66
ivxivv6 vlmOdAsOsvx
c,
P
t--= (OE :ON m Os)
(zoE :ON m Os) (TOE :ON m Os) w
" IWO
DaDVLL3VV9 VN
oo
,- IDIDOODIDVDOVVIVIDVaDVD IDVDaDODVDDVDaDVaDDVD
V33ILLI9I9V9V3L9V3aD99V
o
el
0 (00E :ON m Os)
(66z :ON CET OHS) (86Z :ON CET OHS)
VV
rIdMONAOO IVITIVVO VININASOSVIT
(L6Z :ON CET WS) (96Z :ON CET OHS) (S6Z :ON CET OHS)
13d-OM-179T Z-V
68
oo
r.)
oo
r.)
o (ET
:ON CFI OHS) QM :ON CFI OHS) (OM :ON CFI OHS)
x
NAT 00176ZS:Sd!
¨1
o
rldANNAO0 IVIIIVV9 VINSSASOSVII
el
ci) (ET :ON CFI OHS) QM
:ON CH OHS) (OZEI :ON CFI OHS)
NAT
66E6ZS:Sd!
rldA1NOAO0 IVIIIVVH VII-THSASOSVII
c.)
Pi (ZI ET :ON CFI OHS) (I
1E1 :ON CFI OHS) ((NET :ON CFI OHS)
NAT
L6E6ZS:Sd!
rldANNAO0 IVIIIVV9 VINSSASOSVII
(ZOEI :ON CFI OHS) (IOU :ON CFI OHS) (00EI :ON CFI OHS)
NAT
Z8E6ZS:Sd!
rldANNAO0 IVIIIVV9 VINSSASOSVII
(Z6ZI :ON CH OHS) (I 6ZI :ON CH OHS) (06Z1 :ON CH OHS)
VV
I8E6ZS:Sd!
rldA1NOAO0 IVIIIVVH VII-THSASOSVII
(09E :ON CH OHS) (6SE :ON CH OHS) (8SE :ON m Os)
VV k6)
en IldMNOAO0
IVNIVVO VIHOCRSOSVII
1
o 0
I
a, (Lc E :ON CH OHS)
(9SE :ON CH OHS) (SSE :ON m Os)
44
w
IWO DODVIIDVDD
VN c:
.:,
IDIDOODIOVVDVDIVIDVaDVD IDVOYDODVDDVOYDVaDDVD VaLVDIIDIDVDVDIDVOYDODV
,
' (17SE :ON CFI OHS)
(ESE :ON CFI OHS) (ZSE :ON m Os) ,n vv '"
rIcIMONAO0 IVIIIVVH VIHSIASOSVII
0
P
(ISE :ON CFI OHS) (OSE :ON CFI OHS) (617E :ON (II OHS)
w
w
IWO DaDVIIDVDD
VN u'l
IDIDaDDIDVDOVVIVIDVaDVD I3VOYD99V33V3YDVaDVV9 DVDDVIIDIDVDVDIDVOYDODV
(817E :ON CFI OHS) (Lt E :ON CFI OHS) (917E :ON
CH OHS) VV kt4
rIcIANNAO0 IVIIIVVH VII-IIINASOSVII P
(g17 :ON CFI OHS) (1717 :ON CFI OHS) (17 :ON m Os) w
4==
IWO DODVIIDVDV
VN u4
N
IDIDOODIOVVOVVIVIDVaDVD I3VOYD99V33V3YDVaDVV9
DVOVVIIDIDVDVDIDVOYDODV
o,
= N (Z17E :ON CH O(Ti HS)
(T :ON CFI OHS) (017E :ON m OHs)
el rIcIANNAO0
IVIIIVVH VIHSIASOSVII
oo
o
¨1 (6EE :ON CH OHS)
(SEE :ON CFI OHS) (LEE :ON m Os)
44
=
w
el
o IWO 3aDVII3V3L VN w
IDIDOODIOVVOVVIVIDVaDVD I3VOYD99V33V3YDVaDVV9 DVDIaLIDIDVDVDIDVOYDODV
(9EE :ON CH OHS) (SEE :ON CH OHS) (17EE :ON aj Ws)
13d-OM-179T Z-V
06
oo
(.9)
oo
(.9)
oo
ci)
E=1
en
en
en
en
0,1
0
(WET :ON CH OHS) (19ET :ON CH OHS) (09E-1 :ON CH OHS)
VV
S0176ZS: Sol!
dA1N6A66 IVITIVVH VIHSAASOSVIT
oo
(ZSEI :ON CFI OHS) (I SET :ON CFI OHS) (OSET :ON CFI OHS)
el=
VV 170176ZS:S=1!
rldMONAOO IVITIVVO VININASOSVIT
(ZtET :ON CFI OHS) (TtET :ON CFI OHS) (017ET :ON CFI OHS)
VV
0176ZS:Sd!
rldMNOAO0 IVITIVVH VIHICEASOSVIT
13d-0M-179T Z-V
A-2164-WO-PCT
0
t..)
Table 4B. Exemplary CDRH1, CDRH2, and CDRH3 Nucleotide and Amino Acid
Sequences o
,-,
oe
i-J
QiAbiiiiii iiiiiiiiIA).0
COMM1111112p!i!i!i!i!i!i!i!i!i!i!i!i!i!i!i!i!i!i!i!i!i!i!i!i!i!i!i!i!iiiicpRini
iiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiii
iiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiicMpiiiiiiiiiiiii
iiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiniiiiiiii -4
=
AACTATGGCATGCAC GCTATATGGTTTGATGCAAGTGA
GATTTGGCGATTTTTGGAGTGGT o
--4
TAAATACTATGCAGACGCCGTGA CCCCGACTAC
NA
rn AGGGC
o
'I (SEQ ID NO: 361) (SEQ ID NO: 362) (SEQ ID
NO: 363)
NYGMH AIWFDASDKYYADAVKG
DLAIFGVVPDY
C:4 AA
(SEQ ID NO: 364) (SEQ ID NO: 365) (SEQ ID
NO: 366)
AACTATGGCATGCAC GCTATATGGTTTGATGCAAGTGA
GATTTGGCGATTTTTGGAGTGGT
TAAATACTATGCAGACGCCGTGA CCCCGACTAC
NA
.71. AGGGC
P
o
'I (SEQ ID NO: 367) (SEQ ID NO: 368) (SEQ ID
NO: 369) o
.
NYGMH AIWFDASDKYYADAVKG
DLAIFGVVPDY .
r.,
PI AA
,
(SEQ ID NO: 370) (SEQ ID NO: 371) (SEQ ID
NO: 372) .
r.,
AACTATGGCATGCAC GCTATATGGTTTGATGCAAGTGA
GATTTGGCGATTTTTGGAGTGGT .
,
,
TAAATACTATGCAGACGCCGTGA CCCCGACTAC
,
NA
,
rn AGGGC
(-1
,
'I (SEQ ID NO: 373) (SEQ ID NO: 374) (SEQ ID
NO: 375)
NYGMH AIWFDASDKYYADAVKG
DLAIFGVVPDY
C:4 AA
(SEQ ID NO: 376) (SEQ ID NO: 377) (SEQ ID
NO: 378)
AACTATGGCATGCAC GCTATATGGTTTGATGCAAGTGA
GATTTGGCGATTTTTGGAGTGGT
TAAATACTATGCAGACGCCGTGA CCCCGACTAC
NA
o AGGGC
o
'I (SEQ ID NO: 379) (SEQ ID NO: 380) (SEQ ID
NO: 381) Iv
c:,
n
NYGMH AIWFDASDKYYADAVKG
DLAIFGVVPDY
C:4 AA
1-3
(SEQ ID NO: 382) (SEQ ID NO: 383) (SEQ ID
NO: 384)
cp
AACTATGGCATGCAC GCTATATGGTTTGATGCAAGTGA
GATTTGGCGATTTTTGGAGTGGT n.)
,--i
o
fl TAAATACTATGCAGACGCCGTGA CCCCGACTAC
oe
=
NA 'a
AGGGC
c,.)
t^1 (SEQ ID NO: 385) (SEQ ID NO: 386) (SEQ ID
NO: 387) oe
o
oe
91
A-2164-WO-PCT
NYGMH AIWFDASDKYYADAVKG
DLAIFGVVPDY
AA
(SEQ ID NO: 388) (SEQ ID NO: 389) (SEQ ID
NO: 390)
AACTATGGCATGCAC GCTATATGGTTTGATGCAAGTGA
GATTTGGCGATTTTTGGAGTGGT 0
n.)
TAAATACTATGCAGACGCCGTGA CCCCGACTAC
o
NA
oe
.7r AGGGC
`z. (SEQ ID NO: 391) (SEQ ID NO: 392) (SEQ ID
NO: 393) -4
=
o
NYGMH AIWFDASDKYYADAVKG
DLAIFGVVPDY o
AA
-4
(SEQ ID NO: 394) (SEQ ID NO: 395) (SEQ ID
NO: 396)
AACTATGGCATGCAC GCTATATGGTTTGATGCAAGTGA
GATTTGGCGATTTTTGGAGTGGT
TAAATACTATGCAGACGCCGTGA CCCCGACTAC
NA
o AGGGC
=
`z. (SEQ ID NO: 397) (SEQ ID NO: 398) (SEQ ID
NO: 399)
=
NYGMH AIWFDASDKYYADAVKG
DLAIFGVVPDY
5 AA
(SEQ ID NO: 400) (SEQ ID NO: 401) (SEQ ID
NO: 402)
AACTATGGCATGCAC GCTATATGGTTTGATGCAAGTGA
GATTTGGCGATTTTTGGAGTGGT p
TAAATACTATGCAGACGCCGTGA CCCCGACTAC
NA .
re) AGGGC
.
=
,
`z. (SEQ ID NO: 403) (SEQ ID NO: 404) (SEQ ID
NO: 405) ..
NYGMH AIWFDASDKYYADAVKG
DLAIFGVVPDY
PI AA
,
,0
(SEQ ID NO: 406) (SEQ ID NO: 407) (SEQ ID
NO: 408) ,
,
,
AACTATGGCATGCAC GCTATATGGTTTGATGCAAGTGA
GATTTGGCGATTTTTGGAGTGGT
,
TAAATACTATGCAGACGCCGTGA CCCCGACTAC
NA
co AGGGC
,--i
fl (SEQ ID NO: 409) (SEQ ID NO: 410) (SEQ ID
NO: 411)
NYGMH AIWFDASDKYYADAVKG
DLAIFGVVPDY
=,,i AA
(SEQ ID NO: 412) (SEQ ID NO: 413) (SEQ ID
NO: 414)
AACTATGGCATGCAC GCTATATGGTTTGATGCAAGTGA
GATTTGGCGATTTTTGGAGTGGT
TAAATACTATGCAGACGCCGTGA CCCCGACTAC
00
NA
n
.7r AGGGC
1-3
fl (SEQ ID NO: 415) (SEQ ID NO: 416) (SEQ ID
NO: 417)
=
cp
NYGMH AIWFDASDKYYADAVKG
DLAIFGVVPDY w
5 AA
o
(SEQ ID NO: 418) (SEQ ID NO: 419) (SEQ ID
NO: 420) oe
'a
oe
cr
oe
92
A-2164-WO-PCT
AACTATGGCATGCAC GCTATATGGTTTGATGCAAGTGA
GATTTGGCGATTTTTGGAGTGGT
NA TAAATACTATGCAGACGCCGTGA CCCCGACTAC
AGGGC
0
n (SEQ ID NO: 421) (SEQ ID NO: 422) (SEQ ID
NO: 423) o
=
NYGMH AIWFDASDKYYADAVKG
DLAIFGVVPDY oe
AA
i-J
(SEQ ID NO: 424) (SEQ ID NO: 425) (SEQ ID
NO: 426) c,.)
-4
o
AACTATGGCATGCAC GCTATATGGTTTGATGCAAGTGA
GATTTGGCGATTTTTGGAGTGGT
-4
TAAATACTATGCAGACGCCGTGA CCCCGACTAC
NA
in AGGGC
,--i
n (SEQ ID NO: 427) (SEQ ID NO: 428) (SEQ ID
NO: 429)
=
NYGMH AIWFDASDKYYADAVKG
DLAIFGVVPDY
5 AA
(SEQ ID NO: 430) (SEQ ID NO: 431) (SEQ ID
NO: 432)
AACTATGGCATGCAC GCTATATGGTTTGATGCAAGTGA
GATTTGGCGATTTTTGGAGTGGT
TAAATACTATGCAGACGCCGTGA CCCCGACTAC
NA
,--i AGGGC
re)
P
n (SEQ ID NO: 433) (SEQ ID NO: 434) (SEQ ID
NO: 435) .
5 AA
NYGMH AIWFDASDKYYADAVKG
DLAIFGVVPDY .
,
(SEQ ID NO: 436) (SEQ ID NO: 437) (SEQ ID
NO: 438) ..'
AACTATGGCATGCAC GCTATATGGTTTGATGCAAGTGA
GATCTGGCGATTTTTGGAGTGAT .
,
TAAATACTATGCAGACGCCGTGA TCCCGACTAC
'
,
NA
o
o AGGGC ' n
(SEQ ID NO: 439) (SEQ ID NO: 440)
(SEQ ID NO: 441)
=
NYGMH AIWFDASDKYYADAVKG
DLAIFGVIPDY
5 AA
(SEQ ID NO: 442) (SEQ ID NO: 443) (SEQ ID
NO: 444)
AACTATGGCATGCAC GCTATATGGTTTGATGCAAGTGA
GATTTGGCGATTTTTGGAGTGGT
TAAATACTATGCAGACGCCGTGA CCCCGACTAC
NA
co AGGGC
fl (SEQ ID NO: 445) (SEQ ID NO: 446) (SEQ ID
NO: 447)
NYGMH AIWFDASDKYYADAVKG
DLAIFGVVPDY n
=,,i
AA 1-3
(SEQ ID NO: 448) (SEQ ID NO: 449) (SEQ ID
NO: 450)
cp
re) AACTATGGCATGCAC GCTATATGGTTTGATGCAAGTGA
GATTTGGCGATTTTTGGAGTGGT n.)
o
n TAAATACTATGCAGACGCCGTGA CCCCGACTAC
oe
NA
'a
C.7 AGGGC
c,.)
(-1 r (SEQ ID NO: 451) (SEQ ID NO: 452) (SEQ ID
NO: 453) oe
cr
oe
93
A-2164-WO-PCT
NYGMH AIWFDASDKYYADAVKG
DLAIFGVVPDY
AA
(SEQ ID NO: 454) (SEQ ID NO: 455) (SEQ ID
NO: 456)
AACTATGGCATGCAC GCTATATGGTTTGATGCGTCTGA
GATCTTGCGATTTTTGGAGTGGT 0
n.)
CAAATACTATGCAGACGCCGTGA CCCCGACTAC
o
NA
oe
,--i AGGGC
n (SEQ ID NO: 457) (SEQ ID NO: 458) (SEQ ID
NO: 459) -4
=
o
NYGMH AIWFDASDKYYADAVKG
DLAIFGVVPDY o
AA
-4
(SEQ ID NO: 460) (SEQ ID NO: 461) (SEQ ID
NO: 462)
AACTATGGCATGCAC GCTATATGGTTTGATGCGTCTGA
GATCTTGCGATTTTTGGAGTGGT
CAAATACTATGCAGACGCCGTGA CCCCGACTAC
NA
,--i AGGGC
=
`z. (SEQ ID NO: 463) (SEQ ID NO: 464) (SEQ ID
NO: 465)
=
NYGMH AIWFDASDKYYADAVKG
DLAIFGVVPDY
5 AA
(SEQ ID NO: 466) (SEQ ID NO: 467) (SEQ ID
NO: 468)
AACTATGGCATGCAC GCTATATGGTTTGATGCGTCTGA
GATCTTGCGATTTTTGGAGTGGT p
CAAATACTATGCAGACGCCGTGA CCCCGACTAC
NA .
o AGGGC
.
n (SEQ ID NO: 469) (SEQ ID NO: 470) (SEQ ID
NO: 471) ..
NYGMH AIWFDASDKYYADAVKG
DLAIFGVVPDY
PI AA
,
,0
(SEQ ID NO: 472) (SEQ ID NO: 473) (SEQ ID
NO: 474) ,
,
,
AACTATGGCATGCAC GCTATATGGTTTGATGCAAGTGA
GATTTGGCGATTTTTGGAGTGGT
,
TAAATACTATGCAGACGCCGTGA CCCCGACTAC
NA
co AGGGC
=
fl (SEQ ID NO: 475) (SEQ ID NO: 476) (SEQ ID
NO: 477)
NYGMH AIWFDASDKYYADAVKG
DLAIFGVVPDY
=,,i AA
(SEQ ID NO: 478) (SEQ ID NO: 479) (SEQ ID
NO: 480)
AACTATGGCATGCAC GCTATATGGTTTGATGCAAGTGA
GATTTGGCGATTTTTGGAGTGGT
TAAATACTATGCAGACGCCGTGA CCCCGACTAC
00
NA
n
x AGGGC
=
1-3
`z. (SEQ ID NO: 481) (SEQ ID NO: 482) (SEQ ID
NO: 483)
=
cp
NYGMH AIWFDASDKYYADAVKG
DLAIFGVVPDY w
5 AA
o
(SEQ ID NO: 484) (SEQ ID NO: 485) (SEQ ID
NO: 486) oe
'a
oe
cr
oe
94
A-2164-WO-PCT
AACTATGGCATGCAC GCTATATGGTTTGATGCAAGTGA
GATATTGCGATTTTTGGAGTGGT
NA TAAATACTATGCAGACGCCGTGA CCCCGACTAC
AGGGC
0
re)
l=.)
fl (SEQ ID NO: 487) (SEQ ID NO: 488) (SEQ ID
NO: 489) o
=
NYGMH AIWFDASDKYYADAVKG
DIAIFGVVPDY oe
AA
i-J
(SEQ ID NO: 490) (SEQ ID NO: 491) (SEQ ID
NO: 492) c,.)
-4
o
AACTATGGCATGCAC GCTATATGGTTTGATGCAAGTGA
GATATTGCGATTTTTGGAGTGGT vo
-4
TAAATACTATGCAGACGCCGTGA CCCCGACTAC
NA
.7r AGGGC
.7r
fl (SEQ ID NO: 493) (SEQ ID NO: 494) (SEQ ID
NO: 495)
=
NYGMH AIWFDASDKYYADAVKG
DIAIFGVVPDY
5 AA
(SEQ ID NO: 496) (SEQ ID NO: 497) (SEQ ID
NO: 498)
AACTATGGCATGCAC GCTATATGGTTTGATGCAAGTGA
GATTTGGCGATTTTTGGAGTGGT
TAAATACTATGCAGACGCCGTGA CCCCGACTAC
NA
o AGGGC
fl (SEQ ID NO: 499) (SEQ ID NO: 500) (SEQ ID
NO: 501) .
5 AA
NYGMH AIWFDASDKYYADAVKG
DLAIFGVVPDY .
,
(SEQ ID NO: 502) (SEQ ID NO: 503) (SEQ ID
NO: 504) ..'
AACTATGGCATGCAC GCTATATGGTTTGATGCAAGTGA
GATTTGGCGATTTTTGGAGTGGT .
,
TAAATACTATGCAGACGCCGTGA CCCCGACTAC
'
,
NA
o
o AGGGC ' `z.
(SEQ ID NO: 505) (SEQ ID NO: 506)
(SEQ ID NO: 507)
=
NYGMH AIWFDASDKYYADAVKG
DLAIFGVVPDY
5 AA
(SEQ ID NO: 508) (SEQ ID NO: 509) (SEQ ID
NO: 510)
AACTATGGCATGCAC GCTATATGGTTTGATGCAAGTGA
GATTTGGCGATTTTTGGAGTGGT
TAAATACTATGCAGACGCCGTGA CCCCGACTAC
NA
AGGGC
,--i
fl (SEQ ID NO: 511) (SEQ ID NO: 512) (SEQ ID
NO: 513)
NYGMH AIWFDASDKYYADAVKG
DLAIFGVVPDY n
=,,i
AA 1-3
(SEQ ID NO: 514) (SEQ ID NO: 515) (SEQ ID
NO: 516)
cp
AACTATGGCATGCAC GCTATATGGTTTGATGCAAGTGA
GATTTGGCGATTTTTGGAGTGGT n.)
o
fl TAAATACTATGCAGACGCCGTGA CCCCGACTAC
oe
NA
'a
C.7 AGGGC
c,.)
c4 o (SEQ ID NO: 517) (SEQ ID NO: 518) (SEQ ID
NO: 519) oe
cr
oe
A-2164-WO-PCT
NYGMH AIWFDASDKYYADAVKG
DLAIFGVVPDY
AA
(SEQ ID NO: 520) (SEQ ID NO: 521) (SEQ ID
NO: 522)
AACTATGGCATGCAC GCTATATGGTTTGATGCAAGTGA
GATTTGGCGATTTTTGGAGTGGT 0
n.)
TAAATACTATGCAGACGCCGTGA CCCCGACTAC
o
NA
oe
N AGGGC
n (SEQ ID NO: 523) (SEQ ID NO: 524) (SEQ ID
NO: 525) -4
=
o
NYGMH AIWFDASDKYYADAVKG
DLAIFGVVPDY o
AA
-4
(SEQ ID NO: 526) (SEQ ID NO: 527) (SEQ ID
NO: 528)
AACTATGGCATGCAC GCTATATGGTTTGATGCAAGTGA
GATTTGGCGATTTTTGGAGTGGT
TAAATACTATGCAGACGCCGTGA CCCCGACTAC
NA
oe AGGGC
re)
n (SEQ ID NO: 529) (SEQ ID NO: 530) (SEQ ID
NO: 531)
=
NYGMH AIWFDASDKYYADAVKG
DLAIFGVVPDY
5 AA
(SEQ ID NO: 532) (SEQ ID NO: 533) (SEQ ID
NO: 534)
AACTATGGCATGCAC GCTATATGGTTTGATGCAAGTGA
GATTTGGCGATTTTTGGAGTGGT p
TAAATACTATGCAGACGCCGTGA CCCCGACTAC
NA .
.7r AGGGC
.
n (SEQ ID NO: 535) (SEQ ID NO: 536) (SEQ ID
NO: 537) ..
NYGMH AIWFDASDKYYADAVKG
DLAIFGVVPDY
PI AA
,
,0
(SEQ ID NO: 538) (SEQ ID NO: 539) (SEQ ID
NO: 540) ,
,
,
AACTATGGCATGCAC GCTATATGGTTTGATGCAAGTGA
GATTTGGCGATTTTTGGAGTGGT
,
TAAATACTATGCAGACGCCGTGA CCCCGACTAC
NA
N AGGGC
R (SEQ ID NO: 541) (SEQ ID NO: 542) (SEQ ID
NO: 543)
NYGMH AIWFDASDKYYADAVKG
DLAIFGVVPDY
=,,i AA
(SEQ ID NO: 544) (SEQ ID NO: 545) (SEQ ID
NO: 546)
AACTATGGCATGCAC GCTATATGGTTTGATGCAAGTGA
GATTTGGCGATTTTTGGAGTGGT
TAAATACTATGCAGACGCCGTGA CCCCGACTAC
00
NA
n
,--i AGGGC
1-3
.7r
n (SEQ ID NO: 547) (SEQ ID NO: 548) (SEQ ID
NO: 549)
=
cp
NYGMH AIWFDASDKYYADAVKG
DLAIFGVVPDY w
5 AA
o
(SEQ ID NO: 550) (SEQ ID NO: 551) (SEQ ID
NO: 552) oe
'a
oe
cr
oe
96
A-2164-WO-PCT
AACTATGGCATGCAC GCTATATGGTTTGATGCAAGTGA
GATATTGCGATTTTTGGAGTGTTT
NA TAAATACTATGCAGACGCCGTGA CCCGACTAC
rl AGGGC
0
=
n.)
n (SEQ ID NO: 553) (SEQ ID NO: 554) (SEQ ID
NO: 555) o
=
NYGMH AIWFDASDKYYADAVKG
DIAIFGVFPDY oe
AA
i-J
(SEQ ID NO: 556) (SEQ ID NO: 557) (SEQ ID
NO: 558) c,.)
-4
o
AACTATGGCATGCAC GCTATATGGTTTGATGCAAGTGA
GATATTGCGATTTTTGGAGTGTTT o
-4
TAAATACTATGCAGACGCCGTGA CCCGACTAC
NA
rl AGGGC
=
`z. (SEQ ID NO: 559) (SEQ ID NO: 560) (SEQ ID
NO: 561)
=
NYGMH AIWFDASDKYYADAVKG
DIAIFGVFPDY
5 AA
(SEQ ID NO: 562) (SEQ ID NO: 563) (SEQ ID
NO: 564)
AACTATGGCATGCAC GCTATATGGTTTGATGCAAGTGA
GATATTGCGATTTTTGGAGTGGT
TAAATACTATGCAGACGCCGTGA CCCCGACTAC
NA
in AGGGC
rl
P
n (SEQ ID NO: 565) (SEQ ID NO: 566) (SEQ ID
NO: 567) .
5 AA
NYGMH AIWFDASDKYYADAVKG
DIAIFGVVPDY .
,
(SEQ ID NO: 568) (SEQ ID NO: 569) (SEQ ID
NO: 570) ..'
AACTATGGCATGCAC GCTATATGGTTTGATGCAAGTGA
GATATTGCGATTTTTGGAGTGGT .
,
TAAATACTATGCAGACGCCGTGA CCCCGACTAC
'
,
NA
o
re) AGGGC
' .7r ,
n (SEQ ID NO: 571) (SEQ ID NO: 572) (SEQ ID
NO: 573)
=
NYGMH AIWFDASDKYYADAVKG
DIAIFGVVPDY
5 AA
(SEQ ID NO: 574) (SEQ ID NO: 575) (SEQ ID
NO: 576)
AACTATGGCATGCAC GCTATATGGTTTGATGCAAGTGA
GATATTGCGATTTTTGGAGTGTTT
TAAATACTATGCAGACGCCGTGA CCCGACTAC
NA
re) AGGGC
,--i
fl (SEQ ID NO: 577) (SEQ ID NO: 578) (SEQ ID
NO: 579)
NYGMH AIWFDASDKYYADAVKG
DIAIFGVFPDY n
=,,i
AA 1-3
(SEQ ID NO: 580) (SEQ ID NO: 581) (SEQ ID
NO: 582)
cp
AACTATGGCATGCAC GCTATATGGTTTGATGCAAGTGA
GATATTGCGATTTTTGGAGTGTTT n.)
,--i
o
n TAAATACTATGCAGACGCCGTGA CCCGACTAC
oe
NA
'a
C.7 AGGGC
c,.)
el r (SEQ ID NO: 583) (SEQ ID NO: 584) (SEQ ID
NO: 585) oe
cr
oe
97
A-2164-WO-PCT
NYGMH AIWFDASDKYYADAVKG
DIAIFGVFPDY
AA
(SEQ ID NO: 586) (SEQ ID NO: 587) (SEQ ID
NO: 588)
AACTATGGCATGCAC GCTATATGGTTTGATGCAAGTGA
GATATTGCGATTTTTGGAGTGTTT 0
n.)
TAAATACTATGCAGACGCCGTGA CCCGACTAC
o
NA
oe
,--i AGGGC
fl (SEQ ID NO: 589) (SEQ ID NO: 590) (SEQ ID
NO: 591) -4
=
o
NYGMH AIWFDASDKYYADAVKG
DIAIFGVFPDY o
AA
-4
(SEQ ID NO: 592) (SEQ ID NO: 593) (SEQ ID
NO: 594)
AACTATGGCATGCAC GCTATATGGTTTGATGCAAGTGA
GATATTGCGATTTTTGGAGTGAT
TAAATACTATGCAGACGCCGTGA CCCCGACTAC
NA
o AGGGC
=
fl (SEQ ID NO: 595) (SEQ ID NO: 596) (SEQ ID
NO: 597)
=
NYGMH AIWFDASDKYYADAVKG
DIAIFGVIPDY
5 AA
(SEQ ID NO: 598) (SEQ ID NO: 599) (SEQ ID
NO: 600)
AACTATGGCATGCAC GCTATATGGTTTGATGCAAGTGA
GATATTGCGATTTTTGGAGTGAT p
TAAATACTATGCAGACGCCGTGA CCCCGACTAC
NA .
o
AGGGC .
=
,
`z. (SEQ ID NO: 601) (SEQ ID NO: 602) (SEQ ID
NO: 603) ..
NYGMH AIWFDASDKYYADAVKG
DIAIFGVIPDY .
PI AA
,
,0
(SEQ ID NO: 604) (SEQ ID NO: 605) (SEQ ID
NO: 606) ,
,
,
AACTATGGCATGCAC GCTATATGGTTTGATGCAAGTGA
GATTTGGCGATTTTTGGAGTGGT
,
TAAATACTATGCAGACGCCGTGA CCCCGACTAC
NA
N AGGGC
.7r
fl (SEQ ID NO: 607) (SEQ ID NO: 608) (SEQ ID
NO: 609)
NYGMH AIWFDASDKYYADAVKG
DLAIFGVVPDY
=,,i AA
(SEQ ID NO: 610) (SEQ ID NO: 611) (SEQ ID
NO: 612)
AACTATGGCATGCAC GCTATATGGTTTGATGCAAGTGA
GATCAGGCGATTTTTGGAGTGGT
TAAATACTATGCAGACGCCGTGA CCCCGATTAC
00
NA
n
x AGGGC
.7r
1-3
fl (SEQ ID NO: 613) (SEQ ID NO: 614) (SEQ ID
NO: 615)
=
cp
NYGMH AIWFDASDKYYADAVKG
DQAIFGVVPDY w
5 AA
o
(SEQ ID NO: 616) (SEQ ID NO: 617) (SEQ ID
NO: 618) oe
'a
oe
cr
oe
98
A-2164-WO-PCT
AACTATGGCATGCAC GCTATATGGTTTGATGCAAGTGA
GATATTGCGATTTTTGGAGTGGT
NA TAAATACTATGCAGACGCCGTGA CCCCGACTAC
o
AGGGC 0
n (SEQ ID NO: 619) (SEQ ID NO: 620) (SEQ ID
NO: 621) o
=
NYGMH AIWFDASDKYYADAVKG
DIAIFGVVPDY oe
AA
i-J
(SEQ ID NO: 622) (SEQ ID NO: 623) (SEQ ID
NO: 624) c,.)
-4
o
AACTATGGCATGCAC GCTATATGGTTTGATGCAAGTGA
GATTTGGCGATTTTTGGAGTGGT o
-4
TAAATACTATGCAGACGCCGTGA CCCCGACTAC
NA
N AGGGC
.7r
`z. (SEQ ID NO: 625) (SEQ ID NO: 626) (SEQ ID
NO: 627)
=
NYGMH AIWFDASDKYYADAVKG
DLAIFGVVPDY
5 AA
(SEQ ID NO: 628) (SEQ ID NO: 629) (SEQ ID
NO: 630)
AACTATGGCATGCAC GCTATATGGTTTGATGCAAGTGA
GATCAGGCGATTTTTGGAGTGGT
TAAATACTATGCAGACGCCGTGA CCCCGATTAC
NA
o AGGGC
.7r
P
`z. (SEQ ID NO: 631) (SEQ ID NO: 632) (SEQ ID
NO: 633) .
5 AA
NYGMH AIWFDASDKYYADAVKG
DQAIFGVVPDY .
,
(SEQ ID NO: 634) (SEQ ID NO: 635) (SEQ ID
NO: 636) ..'
AACTATGGCATGCAC GCTATATGGTTTGATGCAAGTGA
GATTTGGCGATTTTTGGAGTGGT .
,
TAAATACTATGCAGACGCCGTGA CCCCGACTAC
'
,
NA
o
in AGGGC
' = ,
n (SEQ ID NO: 637) (SEQ ID NO: 638) (SEQ ID
NO: 639)
=
NYGMH AIWFDASDKYYADAVKG
DLAIFGVVPDY
5 AA
(SEQ ID NO: 640) (SEQ ID NO: 641) (SEQ ID
NO: 642)
AACTATGGCATGCAC GCTATATGGTTTGATGCAAGTGA
GATTTGGCGATTTTTGGAGTGGT
TAAATACTATGCAGACGCCGTGA CCCCGACTAC
NA
in AGGGC
=
`z. (SEQ ID NO: 643) (SEQ ID NO: 644) (SEQ ID
NO: 645)
NYGMH AIWFDASDKYYADAVKG
DLAIFGVVPDY n
=,,i
AA 1-3
(SEQ ID NO: 646) (SEQ ID NO: 647) (SEQ ID
NO: 648)
cp
.7r AACTATGGCATGCAC GCTATATGGTTTGATGCAAGTGA
GATATTGCGATTTTTGGAGTGGT n.)
o
n TAAATACTATGCAGACGCCGTGA CCCCGACTAC
oe
NA
'a
C.7 AGGGC
c,.)
c4 c (SEQ ID NO: 649) (SEQ ID NO: 650) (SEQ ID
NO: 651) oe
cr
oe
99
A-2164-WO-PCT
NYGMH AIWFDASDKYYADAVKG
DIAIFGVVPDY
AA
(SEQ ID NO: 652) (SEQ ID NO: 653) (SEQ ID
NO: 654)
AACTATGGCATGCAC GCTATATGGTTTGATGCAAGTGA
GATTTGGCGATTTTTGGAGTGGT 0
n.)
TAAATACTATGCAGACGCCGTGA CCCCGACTAC
o
NA
oe
.7r AGGGC
re)
W
fl (SEQ ID NO: 655) (SEQ ID NO: 656) (SEQ ID
NO: 657) -4
=
o
NYGMH AIWFDASDKYYADAVKG
DLAIFGVVPDY o
AA
-4
(SEQ ID NO: 658) (SEQ ID NO: 659) (SEQ ID
NO: 660)
AACTATGGCATGCAC GCTATATGGTTTGATGCAAGTGA
GATATTGCGATTTTTGGAGTGGT
TAAATACTATGCAGACGCCGTGA CCCCGACTAC
NA
o AGGGC
re)
fl (SEQ ID NO: 661) (SEQ ID NO: 662) (SEQ ID
NO: 663)
=
NYGMH AIWFDASDKYYADAVKG
DIAIFGVVPDY
5 AA
(SEQ ID NO: 664) (SEQ ID NO: 665) (SEQ ID
NO: 666)
AACTATGGCATGCAC GCTATATGGTTTGATGCGTACGG
GATCAGACGATTTTTGGAGTGGT p
TAAATACTATGCAGACGCCGTGA CCCCGACTAC
NA .
N AGGGC
.
=
,
fl (SEQ ID NO: 667) (SEQ ID NO: 668) (SEQ ID
NO: 669) ..
NYGMH AIWFDAYGKYYADAVKG
DQTIFGVVPDY
PI AA
,
,0
(SEQ ID NO: 670) (SEQ ID NO: 671) (SEQ ID
NO: 672) ,
,
,
AACTATGGCATGCAC GCTATATGGTTTGATGCGTACGG
GATCAGACGATTTTTGGAGTGGT
,
TAAATACTATGCAGACGCCGTGA CCCCGACTAC
NA
N AGGGC
=
`z. (SEQ ID NO: 673) (SEQ ID NO: 674) (SEQ ID
NO: 675)
NYGMH AIWFDAYGKYYADAVKG
DQTIFGVVPDY
=,,i AA
(SEQ ID NO: 676) (SEQ ID NO: 677) (SEQ ID
NO: 678)
AACTATGGCATGCAC GCTATATGGTTTGATGCGTACGG
GATAAGACGATTTTTGGAGTGGT
TAAATACTATGCAGACGCCGTGA CCCCGACTAC
00
NA
n
,--i AGGGC
1-3
fl (SEQ ID NO: 679) (SEQ ID NO: 680) (SEQ ID
NO: 681)
=
cp
NYGMH AIWFDAYGKYYADAVKG
DKTIFGVVPDY w
5 AA
o
(SEQ ID NO: 682) (SEQ ID NO: 683) (SEQ ID
NO: 684) oe
'a
oe
cr
oe
100
A-2164-WO-PCT
AACTATGGCATGCAC GCTATATGGTTTGATGCGTACGG
GATAAGACGATTTTTGGAGTGGT
NA TAAATACTATGCAGACGCCGTGA CCCCGACTAC
AGGGC
0
n (SEQ ID NO: 685) (SEQ ID NO: 686) (SEQ ID
NO: 687) o
=
NYGMH AIWFDAYGKYYADAVKG
DKTIFGVVPDY oe
AA
i-J
(SEQ ID NO: 688) (SEQ ID NO: 689) (SEQ ID
NO: 690) c,.)
-4
o
AACTATGGCATGCAC GCTATATGGTTTGATGCGTACGG
GATAAGACGATTTTTGGAGTGGT o
-4
TAAATACTATGCAGACGCCGTGA CCCCGACTAC
NA
o AGGGC
,--i
n (SEQ ID NO: 691) (SEQ ID NO: 692) (SEQ ID
NO: 693)
=
NYGMH AIWFDAYGKYYADAVKG
DKTIFGVVPDY
5 AA
(SEQ ID NO: 694) (SEQ ID NO: 695) (SEQ ID
NO: 696)
AACTATGGCATGCAC GCTATATGGTTTGATGCGTACGA
GATAAGTCGATTTTTGGAGTGGT
CAAATACTATGCAGACGCCGTGA CCCCGACTAC
NA
AGGGC
re)
P
n (SEQ ID NO: 697) (SEQ ID NO: 698) (SEQ ID
NO: 699) .
5 AA
NYGMH AIWFDAYDKYYADAVKG
DKSIFGVVPDY .
,
(SEQ ID NO: 700) (SEQ ID NO: 701) (SEQ ID
NO: 702) ..'
AACTATGGCATGCAC GCTATATGGTTTGATGCGTACGA
GATAAGTCGATTTTTGGAGTGGT .
,
CAAATACTATGCAGACGCCGTGA CCCCGACTAC
'
,
NA
o
in AGGGC
' .7r ,
n (SEQ ID NO: 703) (SEQ ID NO: 704) (SEQ ID
NO: 705)
=
NYGMH AIWFDAYDKYYADAVKG
DKSIFGVVPDY
5 AA
(SEQ ID NO: 706) (SEQ ID NO: 707) (SEQ ID
NO: 708)
AACTATGGCATGCAC GCTATATGGTTTGATGCGTACGA
GATCTCGCGATTTTTGGAGTGGT
CAAATACTATGCAGACGCCGTGA CCCCGACTAC
NA
in AGGGC
rn
n (SEQ ID NO: 709) (SEQ ID NO: 710) (SEQ ID
NO: 711)
NYGMH AIWFDAYDKYYADAVKG
DLAIFGVVPDY n
=,,i
AA 1-3
(SEQ ID NO: 712) (SEQ ID NO: 713) (SEQ ID
NO: 714)
cp
re) AACTATGGCATGCAC GCTATATGGTTTGATGCGGCTTT
GATCTCGCGATTTTTGGAGTGGT n.)
o
n CAAATACTATGCAGACGCCGTGA CCCCGACTAC
oe
NA
'a
C.7 AGGGC
c,.)
c4 c (SEQ ID NO: 715) (SEQ ID NO: 716) (SEQ ID
NO: 717) oe
cr
oe
101
A-2164-WO-P CT
NYGMH AIWFDAAFKYYADAVKG
DLAIFGVVPDY
AA
(SEQ ID NO: 718) (SEQ ID NO: 719) (SEQ ID
NO: 720)
NYGMH AIWFDASDKYYADAVKG
DLAIFGVIPDY 0
iPS:529381 AA
n.)
o
(SEQ ID NO: 1293) (SEQ ID NO: 1294) (SEQ ID
NO: 1295) 1¨,
oe
NYGMH AIWFDASDKYYADAVKG
DIAIFGVVPDY
iPS:529382 AA
c,.)
(SEQ ID NO: 1303) (SEQ ID NO: 1304) (SEQ ID
NO: 1305) -4
o
o
NYGMH AIWFDASDKYYADAVKG
DQAIFGVVPDY -4
iPS:529397 AA
(SEQ ID NO: 1313) (SEQ ID NO: 1314) (SEQ ID
NO: 1315)
NYGMH AIWFDASDKYYADAVKG
DLAIFGVIPDY
iPS:529399 AA
(SEQ ID NO: 1323) (SEQ ID NO: 1324) (SEQ ID
NO: 1325)
NYGMH AIWFDASDKYYADAVKG
DIAIFGVVPDY
iPS:529400 AA
(SEQ ID NO: 1333) (SEQ ID NO: 1334) (SEQ ID
NO: 1335)
NYGMH AIWFDASDKYYADAVKG
DLAIFGVVPDY
iPS:529403 AA
(SEQ ID NO: 1343) (SEQ ID NO: 1344) (SEQ ID
NO: 1345)
P
NYGMH AIWFDASDKYYADAVKG
DLAIFGVVPDY .
iPS:529404 AA
.
(SEQ ID NO: 1353) (SEQ ID NO: 1354) (SEQ ID
NO: 1355) .
,
NYGMH AIWFDASDKYYADAVKG DLAIFGVVPDY
' iPS:529405 AA ,,
(SEQ ID NO: 1363) (SEQ ID NO: 1364) (SEQ ID
NO: 1365) .
,
,
,
.
,
,
Iv
n
,-i
cp
t..,
=
oe
'a
oe
c:
oe
102
A-2164-WO-PCT
Table 5. Exemplary Light and Heavy Chain Nucleic Acid ("NA") and Amino Acid
("AA") Sequences
0
Ab Description Type LC HC
oe
GAAATAGTGATGACGCAGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCC
CCAGCCACCCTGTCTGTGTCT TGGGAGGTCCCTGAGACTCTCCTGTGCAGCATCTGGATTCA
CCAGGGGAAAGAGCCACCCT CCTTCAGTAACTATGGCATGCACTGGGTCCGCCAGGCTCCA
CTCCTGCAGGGCCAGTCAGAG GGCGAGGGGCTGGAGTGGGTGGCAGCTATATGGTTTGATGC
TGTTGATAGACACTTAGCCTG AAGTGATAAATACTATGCAGACGCCGTGAAGGGCCGATTCA
GTACCAGCAGAAACCTGGCC CCATCTCCAGAGACAACTCCAAGAACACGCTGTATCTGCAA
AGGCTCCCAGGCTCCTCATCT ATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTG
ACGAAGCAGCCACCAGGGCC TGCGAGAGATTTGGCGATTTTTGGAGTGGTCCCCGACTACT
[hu anti- ACTGGTATCCCAGCCAGGTTC
GGGGCCAGGGAACCCTGGTCACCGTGTCTAGTGCCTCCACC
<huGIPR> AGTGGCAGTGGGTCTGGGAC
AAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAG
2G10.303 AGAGTTCACTCTCACCATCAG
CACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGG
VK3 (1-236) CAGCCTGCAGTCTGAAGATTT
ACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGC
VL]::huKLC TGCAGTTTATTACTGTCAGCA
GCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACA
-CL + GTATCAGAACTGGCCTCTCAC
GTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGC
[Unknown TTTCGGCGGAGGGACCAAGGT
CCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTG
anti-
A N GGAGATCAAACGAACGGTGG
AATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTG
<huGIPR> CTGCACCATCTGTCTTCATCTT
AGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGC
2G10.610 CCCGCCATCTGATGAGCAGTT
CCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTC
VH3 (1-472) GAAATCTGGAACTGCCTCTGT
CCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCC
VH]::huIgG1 TGTGTGCCTGCTGAATAACTT
TGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACC
zSEFL2-2 CTATCCCAGAGAGGCCAAAG
CTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTG
(mAb); LMR TACAGTGGAAGGTGGATAAC
CATAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCA
ID: SS- GCCCTCCAATCGGGTAACTCC
GCACGTACCGTTGCGTCAGCGTCCTCACCGTCCTGCACCAG
26180 CAGGAGAGTGTCACAGAGCA
GACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCCA
GGACAGCAAGGACAGCACCT ACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAA
ACAGCCTCAGCAGCACCCTGA GCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCC
1-d
CGCTGAGCAAAGCAGACTAC CCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTG
GAGAAACACAAAGTCTACGC ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGT
CTGCGAAGTCACCCATCAGGG GGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAG
CCTGAGCTCGCCCGTCACAAA ACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTC
ri GAGCTTCAACAGGGGAGAGT
TATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGG
oe
GT
GGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCAC c7,
oe
103
A-2164-WO-PCT
AACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAA
A
(SEQ ID NO: 12) (SEQ ID NO: 13)
0
EIVMTQ SP ATL SVSPGERATLS QVQLVE SGGGVVQPGRSLRL SCAASGFTFSNYGMHWVRQAP
CRASQSVDRHLAWYQQKPGQ GEGLEWVAAIWFDASDKYYADAVKGRFTISRDNSKNTLYLQ
oe
APRLLIYEAATRATGIPARFSGS MNSLRAEDTAVYYCARDLAIFGVVPDYWGQGTLVTVSSASTK
GS GTEFTL TI S SLQ SEDFAVYYC GP SVFPL AP S SKST S GGTAALGCLVKDYFPEPVTVSWN S
GAL T
QQYQNWPLTFGGGTKVEIKRT SGVHTFPAVLQSSGLY SLSSVVTVP SSSLGTQTYICNVNHKP SN
VAAPSVFIFPPSDEQLKSGTASV TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
AA
VCLLNNFYPREAKVQWKVDN MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCE
ALQSGNSQESVTEQDSKDSTYS EQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI
L SSTLTL SKADYEKHKVYACE SKAKGQPREPQVYTLPP SREEMTKNQVSLTCLVKGFYP SDIAV
VTHQGLSSPVTKSFNRGEC
EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN
VFSCSVMHEALHNHYTQKSLSLSPGK
(SEQ ID NO: 14) (SEQ ID NO: 15)
GAAATAGTGATGACGCAGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCC
CCAGCCACCCTGTCTGTGTCT TGGGAGGTCCCTGAGACTCTCCTGTGCAGCATCTGGATTCA
CCAGGGGAAAGAGCCACCCT CCTTCAGTAACTATGGCATGCACTGGGTCCGCCAGGCTCCA
[hu anti-
h CTCCTGCAGGGCCAGTCAGAG
GGCGAGGGGCTGGAGTGGGTGGCAGCTATATGGTTTGATGC
<uGIPR>
TGTTAACAGACACTTAGCCTG AAGTGATAAATACTATGCAGACGCCGTGAAGGGCCGATTCA
2G10.304
VK3
GTACCAGCAGAAACCTGGCC CCATCTCCAGAGACAACTCCAAGAACACGCTGTATCTGCAA
( 1-236)
VL AGGCTCCCAGGCTCCTCATCT
ATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTG
]::huKLC
ACGAAGCAGCCACCAGGGCC TGCGAGAGATTTGGCGATTTTTGGAGTGGTCCCCGACTACT
-CL +
ACTGGTATCCCAGCCAGGTTC GGGGCCAGGGAACCCTGGTCACCGTGTCTAGTGCCTCCACC
[Unknown
AGTGGCAGTGGGTCTGGGAC AAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAG
anti-
NA AGAGTTCACTCTCACCATCAG CACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGG
<huGIPR>
2G10 610 CAGCCTGCAGTCTGAAGATTT
ACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGC
.
TGCAGTTTATTACTGTCAGCA GCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACA
VH3 (1-472)
GTATCAGAACTGGCCTCTCAC GTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGC
VH1::ImIgG1
TTTCGGCGGAGGGACCAAGGT CCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTG
zSEFL2-2
GGAGATCAAACGAACGGTGG AATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTG
1-3
(mAb); LMR
CTGCACCATCTGTCTTCATCTT AGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGC
f 1 26181 CCCGCCATCTGATGAGCAGTT
CCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTC
GAAATCTGGAACTGCCTCTGT CCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCC
TGTGTGCCTGCTGAATAACTT TGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACC
CTATCCCAGAGAGGCCAAAG CTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTG
oe
cr
oe
104
A-2164-W0- P CT
TACAGTGGAAGGTGGATAAC CATAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCA
GCCCTCCAATCGGGTAACTCC GCACGTACCGTTGCGTCAGCGTCCTCACCGTCCTGCACCAG
CAGGAGAGTGTCACAGAGCA GACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCCA
GGACAGCAAGGACAGCACCT ACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAA
ACAGCCTCAGCAGCACCCTGA GCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCC
CGCTGAGCAAAGCAGACTAC CCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTG
GAGAAACACAAAGTCTACGC ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGT
CTGCGAAGTCACCCATCAGGG GGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAG
CCTGAGCTCGCCCGTCACAAA ACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTC
GAGCTTCAACAGGGGAGAGT TATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGG
GT
GGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCAC
AACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAA
A
(SEQ ID NO: 16) (SEQ ID NO: 17)
EIVMTQ SP ATL SVSPGERATLS QVQLVE SGGGVVQPGRSLRL SCAASGFTFSNYGMHWVRQAP
CRASQSVNRHLAWYQQKPGQ GEGLEWVAAIWFDASDKYYADAVKGRFTISRDNSKNTLYLQ
APRLLIYEAATRATGIPARFSGS MNSLRAEDTAVYYCARDLAIFGVVPDYWGQGTLVTVSSASTK
GS GTEFTL TI S SLQSEDFAVYYC GP SVFPL AP S SKST S GGTAALGCLVKDYFPEPVTVSWN S GAL
T
QQYQNWPLTFGGGTKVEIKRT SGVHTFPAVLQS SGLY SLS SVVTVP S S SLGTQTYICNVNHKP SN
AA VAAPSVFIFPPSDEQLKSGTASV TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
VCLLNNFYPREAKVQWKVDN MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCE
ALQSGNSQESVTEQD SKD STY S EQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI
L SSTLTL SKADYEKHKVYACE SKAKGQPREPQVYTLPP SREEMTKNQVSLTCLVKGFYP SDIAV
VTHQGLSSPVTKSFNRGEC EWE SNGQPENNYKTTPPVLD SD
GSFFLY SKL TVD KSRWQQ GN
VFSCSVMHEALHNHYTQKSLSLSPGK
(SEQ ID NO: 18) (SEQ ID NO: 19)
[hu anti- GAAATAGTGATGACGCAGTCT
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCC
<huGIPR> CCAGCCACCCTGTCTGTGTCT
TGGGAGGTCCCTGAGACTCTCCTGTGCAGCATCTGGATTCA
2G10.323 CCAGGGGAAAGAGCCACCCT
CCTTCAGTAACTATGGCATGCACTGGGTCCGCCAGGCTCCA
VK3 (1-236) CTCCTGCAGGGCCAGTCAGAG
GGCGAGGGGCTGGAGTGGGTGGCAGCTATATGGTTTGATGC
VL]::huKLC NA TGTTCATAGACACTTAGCCTG AAGTGATAAATACTATGCAGACGCCGTGAAGGGCCGATTCA
1-3
-CL + GTACCAGCAGAAACCTGGCC
CCATCTCCAGAGACAACTCCAAGAACACGCTGTATCTGCAA
PI [Unknown AGGCTCCCAGGCTCCTCATCT
ATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTG
g anti- ACGAAGCAGCCACCAGGGCC
TGCGAGAGATTTGGCGATTTTTGGAGTGGTCCCCGACTACT
<huGIPR> ACTGGTATCCCAGCCAGGTTC
GGGGCCAGGGAACCCTGGTCACCGTGTCTAGTGCCTCCACC
2G10.610 AGTGGCAGTGGGTCTGGGAC
AAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAG oe
oe
105
A-2164-WO-PCT
VH3 (1-472) AGAGTTCACTCTCACCATCAG
CACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGG
VH]::huIgG1 CAGCCTGCAGTCTGAAGATTT
ACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGC
zSEFL2-2 TGCAGTTTATTACTGTCAGCA
GCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACA
(mAb); LMR GTATCAGAACTGGCCTCTCAC
GTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGC
ID: SS- TTTCGGCGGAGGGACCAAGGT
CCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTG
26200 GGAGATCAAACGAACGGTGG
AATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTG
CTGCACCATCTGTCTTCATCTT AGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGC
CCCGCCATCTGATGAGCAGTT CCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTC
GAAATCTGGAACTGCCTCTGT CCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCC
TGTGTGCCTGCTGAATAACTT TGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACC
CTATCCCAGAGAGGCCAAAG CTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTG
TACAGTGGAAGGTGGATAAC CATAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCA
GCCCTCCAATCGGGTAACTCC GCACGTACCGTTGCGTCAGCGTCCTCACCGTCCTGCACCAG
CAGGAGAGTGTCACAGAGCA GACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCCA
GGACAGCAAGGACAGCACCT ACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAA
ACAGCCTCAGCAGCACCCTGA GCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCC
CGCTGAGCAAAGCAGACTAC CCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTG
GAGAAACACAAAGTCTACGC ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGT
CTGCGAAGTCACCCATCAGGG GGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAG
CCTGAGCTCGCCCGTCACAAA ACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTC
GAGCTTCAACAGGGGAGAGT TATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGG
GT
GGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCAC
AACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAA
A
(SEQ ID NO: 20) (SEQ ID NO: 21)
EIVMTQSPATLSVSPGERATLS QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMHWVRQAP
CRASQSVHRHLAWYQQKPGQ GEGLEWVAAIWFDASDKYYADAVKGRFTISRDNSKNTLYLQ
APRLLIYEAATRATGIPARFSGS MNSLRAEDTAVYYCARDLAIFGVVPDYWGQGTLVTVSSASTK
GSGTEFTLTISSLQSEDFAVYYC GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALT
QQYQNWPLTFGGGTKVEIKRT SGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN
AA VAAPSVFIFPPSDEQLKSGTASV TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
1-3
VCLLNNFYPREAKVQWKVDN MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCE
ALQSGNSQESVTEQDSKDSTYS EQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI
LSSTLTLSKADYEKHKVYACE SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV
oe
VTHQGLSSPVTKSFNRGEC
EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN
VFSCSVMHEALHNHYTQKSLSLSPGK
oe
oe
106
A-2164-WO-P CT
(SEQ ID NO: 22) (SEQ ID NO: 23)
GAAATAGTGATGACGCAGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCC
CCAGCCACCCTGTCTGTGTCT TGGGAGGTCCCTGAGACTCTCCTGTGCAGCATCTGGATTCA
CCAGGGGAAAGAGCCACCCT CCTTCAGTAACTATGGCATGCACTGGGTCCGCCAGGCTCCA
CTCCTGCAGGGCCAGTCAGAG GGCGAGGGGCTGGAGTGGGTGGCAGCTATATGGTTTGATGC
oe
TGTTGAAAGACACTTAGCCTG AAGTGATAAATACTATGCAGACGCCGTGAAGGGCCGATTCA
GTACCAGCAGAAACCTGGCC CCATCTCCAGAGACAACTCCAAGAACACGCTGTATCTGCAA
AGGCTCCCAGGCTCCTCATCT ATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTG
ACGAAGCAGCCACCAGGGCC TGCGAGAGATTTGGCGATTTTTGGAGTGGTCCCCGACTACT
ACTGGTATCCCAGCCAGGTTC GGGGCCAGGGAACCCTGGTCACCGTGTCTAGTGCCTCCACC
AGTGGCAGTGGGTCTGGGAC AAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAG
[hu anti-
AGAGTTCACTCTCACCATCAG CACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGG
<huGIPR>
CAGCCTGCAGTCTGAAGATTT ACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGC
2G10.309
TGCAGTTTATTACTGTCAGCA GCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACA
VK3 (1-236)
GTATCAGAACTGGCCTCTCAC GTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGC
VL]::huKLC
TTTCGGCGGAGGGACCAAGGT CCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTG
-CL +
GGAGATCAAACGAACGGTGG AATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTG
[Unknown
CTGCACCATCTGTCTTCATCTT AGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGC
anti-
NA CCCGCCATCTGATGAGCAGTT CCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTC
<huGIPR>
GAAATCTGGAACTGCCTCTGT CCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCC
2G10.610
VH3( 1-472)
TGTGTGCCTGCTGAATAACTT TGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACC
CTATCCCAGAGAGGCCAAAG CTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTG
VH]::huIgG1
TACAGTGGAAGGTGGATAAC CATAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCA
zSEFL2-2
GCCCTCCAATCGGGTAACTCC GCACGTACCGTTGCGTCAGCGTCCTCACCGTCCTGCACCAG
(m b), LMR
CAGGAGAGTGTCACAGAGCA GACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCCA
ID: SS-
GGACAGCAAGGACAGCACCT ACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAA
26186
ACAGCCTCAGCAGCACCCTGA GCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCC
CGCTGAGCAAAGCAGACTAC CCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTG
GAGAAACACAAAGTCTACGC ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGT
CTGCGAAGTCACCCATCAGGG GGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAG
CCTGAGCTCGCCCGTCACAAA ACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTC
1-3
GAGCTTCAACAGGGGAGAGT TATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGG
GT
GGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCAC
AACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAA
oe
A
(SEQ ID NO: 24) (SEQ ID NO: 25)
oe
oe
107
A-2164-WO-PCT
EIVMTQSPATLSVSPGERATLS QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMHWVRQAP
CRASQSVERHLAWYQQKPGQ GEGLEWVAAIWFDASDKYYADAVKGRFTISRDNSKNTLYLQ
APRLLIYEAATRATGIPARFSGS MNSLRAEDTAVYYCARDLAIFGVVPDYWGQGTLVTVSSASTK
GSGTEFTLTISSLQSEDFAVYYC GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALT
QQYQNWPLTFGGGTKVEIKRT SGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN
AA VAAPSVFIFPPSDEQLKSGTASV TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
VCLLNNFYPREAKVQWKVDN MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCE
ALQSGNSQESVTEQDSKDSTYS EQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI
LSSTLTLSKADYEKHKVYACE SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV
VTHQGLSSPVTKSFNRGEC
EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN
VFSCSVMHEALHNHYTQKSLSLSPGK
(SEQ ID NO: 26) (SEQ ID NO: 27)
GAAATAGTGATGACGCAGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCC
CCAGCCACCCTGTCTGTGTCT TGGGAGGTCCCTGAGACTCTCCTGTGCAGCATCTGGATTCA
CCAGGGGAAAGAGCCACCCT CCTTCAGTAACTATGGCATGCACTGGGTCCGCCAGGCTCCA
CTCCTGCAGGGCCAGTCAGAG GGCGAGGGGCTGGAGTGGGTGGCAGCTATATGGTTTGATGC
[hu anti- TGTTTTCAGACACTTAGCCTG
AAGTGATAAATACTATGCAGACGCCGTGAAGGGCCGATTCA
<huGIPR> GTACCAGCAGAAACCTGGCC
CCATCTCCAGAGACAACTCCAAGAACACGCTGTATCTGCAA
2G10.316 AGGCTCCCAGGCTCCTCATCT
ATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTG
VK3 (1-236) ACGAAGCAGCCACCAGGGCC
TGCGAGAGATTTGGCGATTTTTGGAGTGGTCCCCGACTACT
VL]::huKLC ACTGGTATCCCAGCCAGGTTC
GGGGCCAGGGAACCCTGGTCACCGTGTCTAGTGCCTCCACC
-CL + AGTGGCAGTGGGTCTGGGAC
AAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAG
[Unknown AGAGTTCACTCTCACCATCAG
CACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGG
anti- NA CAGCCTGCAGTCTGAAGATTT
ACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGC
<huGIPR> TGCAGTTTATTACTGTCAGCA
GCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACA
2G10.610 GTATCAGAACTGGCCTCTCAC
GTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGC
VH3 (1-472) TTTCGGCGGAGGGACCAAGGT
CCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTG
VH]::huIgG1 GGAGATCAAACGAACGGTGG
AATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTG
zSEFL2-2 CTGCACCATCTGTCTTCATCTT
AGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGC
(mAb); LMR CCCGCCATCTGATGAGCAGTT
CCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTC
ID: SS- GAAATCTGGAACTGCCTCTGT
CCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCC
1-3
26193 TGTGTGCCTGCTGAATAACTT
TGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACC
CTATCCCAGAGAGGCCAAAG CTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTG
TACAGTGGAAGGTGGATAAC CATAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCA
oe
GCCCTCCAATCGGGTAACTCC GCACGTACCGTTGCGTCAGCGTCCTCACCGTCCTGCACCAG
CAGGAGAGTGTCACAGAGCA GACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCCA
oe
oe
108
A-2164-WO-PCT
GGACAGCAAGGACAGCACCT ACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAA
ACAGCCTCAGCAGCACCCTGA GCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCC
CGCTGAGCAAAGCAGACTAC CCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTG
GAGAAACACAAAGTCTACGC ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGT
CTGCGAAGTCACCCATCAGGG GGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAG
CCTGAGCTCGCCCGTCACAAA ACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTC
GAGCTTCAACAGGGGAGAGT TATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGG
GT
GGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCAC
AACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAA
A
(SEQ ID NO: 28) (SEQ ID NO: 29)
EIVMTQSPATL SVSPGERATLS QVQLVE SGGGVVQPGRSLRL SCAASGFTFSNYGMHWVRQAP
CRASQSVFRHLAWYQQKPGQA GEGLEWVAAIWFDASDKYYADAVKGRFTISRDNSKNTLYLQ
PRLLIYEAATRATGIPARFSGSG MNSLRAEDTAVYYCARDLAIFGVVPDYWGQGTLVTVSSASTK
SGTEFTLTISSLQSEDFAVYYCQ GP SVFPLAP S SKST S GGTAALGCLVKDYFPEPVTVSWN S GALT
QYQNWPLTFGGGTKVEIKRTV SGVHTFPAVLQSSGLY SLSSVVTVP SSSLGTQTYICNVNHKP SN
AA AAP SVFIFPP SDEQLKSGTASVV
TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
CLLNNFYPREAKVQWKVDNAL MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCE
QSGNSQESVTEQD SKD STY SL S EQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI
STLTLSKADYEKHKVYACEVT SKAKGQPREPQVYTLPP SREEMTKNQVSLTCLVKGFYP SDIAV
HQGL SSPVTKSFNRGEC
EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN
VFSCSVMHEALHNHYTQKSLSLSPGK
(SEQ ID NO: 30) (SEQ ID NO: 31)
[hu anti- GAAATAGTGATGACGCAGTCT
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCC
<huGIPR> CCAGCCACCCTGTCTGTGTCT
TGGGAGGTCCCTGAGACTCTCCTGTGCAGCATCTGGATTCA
2G10.604 CCAGGGGAAAGAGCCACCCT
CCTTCAGTAACTATGGCATGCACTGGGTCCGCCAGGCTCCA
VK3 (1-236) CTCCTGCAGGGCCAGTCAGAG
GGCGAGGGGCTGGAGTGGGTGGCAGCTATATGGTTTGATGC
VL]::huKLC TGTTAACAGACACTTAGCCTG
AAGTGATAAATACTATGCAGACGCCGTGAAGGGCCGATTCA
-CL + GTACCAGCAGAAACCTGGCC
CCATCTCCAGAGACAACTCCAAGAACACGCTGTATCTGCAA
[Unknown NA AGGCTCCCAGGCTCCTCATCT ATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTG
anti- ACGAAGCAGCCACCAGGGCC
TGCGAGAGATTTGGCGATTTTTGGAGTGGTCCCCGACTACT 1-3
<huGIPR> ACTGGTATCCCAGCCAGGGTC
GGGGCCAGGGAACCCTGGTCACCGTGTCTAGTGCCTCCACC
2G10.610 AGTGGCAGTGGGTCTGGGAC
AAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAG
c5 VH3 (1-472) AGAGTTCACTCTCACCATCAG
CACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGG
VH]::huIgG1 CAGCCTGCAGTCTGAAGATTT
ACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGC
zSEFL2-2 TGCAGTTTATTACTGTCAGCA
GCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACA oe
oe
109
A-2164-WO-PCT
(mAb); LMR GTATCAGAACTGGCCTCTCAC
GTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGC
ID: SS- TTTCGGCGGAGGGACCAAGGT
CCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTG
26229 GGAGATCAAACGAACGGTGG
AATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTG
CTGCACCATCTGTCTTCATCTT AGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGC
CCCGCCATCTGATGAGCAGTT CCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTC
GAAATCTGGAACTGCCTCTGT CCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCC
TGTGTGCCTGCTGAATAACTT TGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACC
CTATCCCAGAGAGGCCAAAG CTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTG
TACAGTGGAAGGTGGATAAC CATAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCA
GCCCTCCAATCGGGTAACTCC GCACGTACCGTTGCGTCAGCGTCCTCACCGTCCTGCACCAG
CAGGAGAGTGTCACAGAGCA GACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCCA
GGACAGCAAGGACAGCACCT ACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAA
ACAGCCTCAGCAGCACCCTGA GCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCC
CGCTGAGCAAAGCAGACTAC CCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTG
GAGAAACACAAAGTCTACGC ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGT
CTGCGAAGTCACCCATCAGGG GGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAG
CCTGAGCTCGCCCGTCACAAA ACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTC
GAGCTTCAACAGGGGAGAGT TATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGG
GT
GGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCAC
AACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAA
A
(SEQ ID NO: 32) (SEQ ID NO: 33)
EIVMTQSPATLSVSPGERATLS QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMHWVRQAP
CRASQSVNRHLAWYQQKPGQ GEGLEWVAAIWFDASDKYYADAVKGRFTISRDNSKNTLYLQ
APRLLIYEAATRATGIPARVSGS MNSLRAEDTAVYYCARDLAIFGVVPDYWGQGTLVTVSSASTK
GSGTEFTLTISSLQSEDFAVYYC GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALT
QQYQNWPLTFGGGTKVEIKRT SGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN
VAAPSVFIFPPSDEQLKSGTASV TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
AA
VCLLNNFYPREAKVQWKVDN MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCE
ALQSGNSQESVTEQDSKDSTYS EQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI
LSSTLTLSKADYEKHKVYACE SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV
1-3
VTHQGLSSPVTKSFNRGEC
EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN
VFSCSVMHEALHNHYTQKSLSLSPGK
(SEQ ID NO: 34) (SEQ ID NO: 35)
oe
[hu anti-
NA GAAATAGTGATGACGCAGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCC
" <huGIPR> CCAGCCACCCTGTCTGTGTCT
TGGGAGGTCCCTGAGACTCTCCTGTGCAGCATCTGGATTCA oe
oe
110
A-2164-WO-PCT
2G10.609 CCAGGGGAAAGAGCCACCCT
CCTTCAGTAACTATGGCATGCACTGGGTCCGCCAGGCTCCA
VK3 (1-236) CTCCTGCAGGGCCAGTCAGAG
GGCGAGGGGCTGGAGTGGGTGGCAGCTATATGGTTTGATGC
VL]::huKLC TGTTGAAAGACACTTAGCCTG
AAGTGATAAATACTATGCAGACGCCGTGAAGGGCCGATTCA
-CL + GTACCAGCAGAAACCTGGCC
CCATCTCCAGAGACAACTCCAAGAACACGCTGTATCTGCAA
[Unknown AGGCTCCCAGGCTCCTCATCT
ATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTG
anti- ACGAAGCAGCCACCAGGGCC
TGCGAGAGATTTGGCGATTTTTGGAGTGGTCCCCGACTACT
<huGIPR> ACTGGTATCCCAGCCAGGGTC
GGGGCCAGGGAACCCTGGTCACCGTGTCTAGTGCCTCCACC
2G10.610 AGTGGCAGTGGGTCTGGGAC
AAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAG
VH3 (1-472) AGAGTTCACTCTCACCATCAG
CACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGG
VH]::huIgG1 CAGCCTGCAGTCTGAAGATTT
ACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGC
zSEFL2-2 TGCAGTTTATTACTGTCAGCA
GCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACA
(mAb); LMR GTATCAGAACTGGCCTCTCAC
GTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGC
ID: SS- TTTCGGCGGAGGGACCAAGGT
CCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTG
26234 GGAGATCAAACGAACGGTGG
AATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTG
CTGCACCATCTGTCTTCATCTT AGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGC
CCCGCCATCTGATGAGCAGTT CCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTC
GAAATCTGGAACTGCCTCTGT CCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCC
TGTGTGCCTGCTGAATAACTT TGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACC
CTATCCCAGAGAGGCCAAAG CTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTG
TACAGTGGAAGGTGGATAAC CATAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCA
GCCCTCCAATCGGGTAACTCC GCACGTACCGTTGCGTCAGCGTCCTCACCGTCCTGCACCAG
CAGGAGAGTGTCACAGAGCA GACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCCA
GGACAGCAAGGACAGCACCT ACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAA
ACAGCCTCAGCAGCACCCTGA GCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCC
CGCTGAGCAAAGCAGACTAC CCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTG
GAGAAACACAAAGTCTACGC ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGT
CTGCGAAGTCACCCATCAGGG GGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAG
CCTGAGCTCGCCCGTCACAAA ACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTC
GAGCTTCAACAGGGGAGAGT TATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGG
GT
GGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCAC
AACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAA
1-3
A
(SEQ ID NO: 36) (SEQ ID NO: 37)
EIVMTQSPATLSVSPGERATLS QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMHWVRQAP
oe
AA CRASQSVERHLAWYQQKPGQ GEGLEWVAAIWFDASDKYYADAVKGRFTISRDNSKNTLYLQ
APRLLIYEAATRATGIPARVSGS MNSLRAEDTAVYYCARDLAIFGVVPDYWGQGTLVTVSSASTK
oe
oe
111
A-2164-WO-PCT
GSGTEFTLTISSLQSEDFAVYYC GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALT
QQYQNWPLTFGGGTKVEIKRT SGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN
VAAPSVFIFPPSDEQLKSGTASV TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
VCLLNNFYPREAKVQWKVDN MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCE
ALQSGNSQESVTEQDSKDSTYS EQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI
LSSTLTLSKADYEKHKVYACE SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV
VTHQGLSSPVTKSFNRGEC
EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN
VFSCSVMHEALHNHYTQKSLSLSPGK
(SEQ ID NO: 38) (SEQ ID NO: 39)
GAAATAGTGATGACGCAGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCC
CCAGCCACCCTGTCTGTGTCT TGGGAGGTCCCTGAGACTCTCCTGTGCAGCATCTGGATTCA
CCAGGGGAAAGAGCCACCCT CCTTCAGTAACTATGGCATGCACTGGGTCCGCCAGGCTCCA
CTCCTGCAGGGCCAGTCAGAG GGCGAGGGGCTGGAGTGGGTGGCAGCTATATGGTTTGATGC
TGTTGATAGACACTTAGCCTG AAGTGATAAATACTATGCAGACGCCGTGAAGGGCCGATTCA
h GTACCAGCAGAAACCTGGCC
CCATCTCCAGAGACAACTCCAAGAACACGCTGTATCTGCAA
R>
[u anti-
AGGCTCCCAGGCTCCTCATCT ATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTG
<huGIP
2G10.603 ACGAAGCAGCCACCAGGGCC
TGCGAGAGATTTGGCGATTTTTGGAGTGGTCCCCGACTACT
ACTGGTATCCCAGCCAGGGTC GGGGCCAGGGAACCCTGGTCACCGTGTCTAGTGCCTCCACC
VK3 (1-236)
AGTGGCAGTGGGTCTGGGAC AAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAG
VL]::huKLC
AGAGTTCACTCTCACCATCAG CACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGG
-CL +
CAGCCTGCAGTCTGAAGATTT ACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGC
[Unknown
TGCAGTTTATTACTGTCAGCA GCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACA
anti-
NA GTATCAGAACTGGCCTCTCAC GTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGC
<huGIPR>
TTTCGGCGGAGGGACCAAGGT CCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTG
2G10.610
GGAGATCAAACGAACGGTGG AATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTG
VH3 :huIgG1(1-472)
CTGCACCATCTGTCTTCATCTT AGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGC
VH]:
SEFL2 CCCGCCATCTGATGAGCAGTT
CCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTC
-2
z
GAAATCTGGAACTGCCTCTGT CCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCC
(mAb); LMR
TGTGTGCCTGCTGAATAACTT TGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACC
ID: 26228 SS-
CTATCCCAGAGAGGCCAAAG CTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTG
TACAGTGGAAGGTGGATAAC CATAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCA
1-3
GCCCTCCAATCGGGTAACTCC GCACGTACCGTTGCGTCAGCGTCCTCACCGTCCTGCACCAG
re)
CAGGAGAGTGTCACAGAGCA GACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCCA
`z. GGACAGCAAGGACAGCACCT
ACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAA
oe
ACAGCCTCAGCAGCACCCTGA GCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCC
CGCTGAGCAAAGCAGACTAC CCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTG
oe
oe
112
A-2164-WO-PCT
GAGAAACACAAAGTCTACGC ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGT
CTGCGAAGTCACCCATCAGGG GGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAG
CCTGAGCTCGCCCGTCACAAA ACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTC
GAGCTTCAACAGGGGAGAGT TATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGG
GT
GGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCAC
AACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAA
A
(SEQ ID NO: 40) (SEQ ID NO: 41)
EIVMTQSPATL SVSPGERATLS QVQLVE SGGGVVQPGRSLRL SCAASGFTFSNYGMHWVRQAP
CRASQSVDRHLAWYQQKPGQ GEGLEWVAAIWFDASDKYYADAVKGRFTISRDNSKNTLYLQ
APRLLIYEAATRATGIPARVSGS MNSLRAEDTAVYYCARDLAIFGVVPDYWGQGTLVTVSSASTK
GS GTEFTLTI S SLQ SEDFAVYYC GP SVFPL AP S SKST S GGTAALGCLVKDYFPEPVTVSWN S
GALT
QQYQNWPLTFGGGTKVEIKRT SGVHTFPAVLQSSGLY SLSSVVTVP SSSLGTQTYICNVNHKP SN
VAAPSVFIFPPSDEQLKSGTASV TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
AA
VCLLNNFYPREAKVQWKVDN MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCE
ALQSGNSQESVTEQDSKDSTYS EQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI
L SSTLTL SKADYEKHKVYACE SKAKGQPREPQVYTLPP SREEMTKNQVSLTCLVKGFYP SDIAV
VTHQGLSSPVTKSFNRGEC
EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN
VFSCSVMHEALHNHYTQKSLSLSPGK
(SEQ ID NO: 42) (SEQ ID NO: 43)
[hu anti- GAAATAGTGATGACGCAGTCT
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCC
<huGIPR> CCAGCCACCCTGTCTGTGTCT
TGGGAGGTCCCTGAGACTCTCCTGTGCAGCATCTGGATTCA
2G10.318 CCAGGGGAAAGAGCCACCCT
CCTTCAGTAACTATGGCATGCACTGGGTCCGCCAGGCTCCA
VK3 (1-236) CTCCTGCAGGGCCAGTCAGAG
GGCGAGGGGCTGGAGTGGGTGGCAGCTATATGGTTTGATGC
VL]::huKLC TGTTCTGAGTCACTTAGCCTG
AAGTGATAAATACTATGCAGACGCCGTGAAGGGCCGATTCA
-CL + GTACCAGCAGAAACCTGGCC
CCATCTCCAGAGACAACTCCAAGAACACGCTGTATCTGCAA
[Unknown AGGCTCCCAGGCTCCTCATCT
ATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTG
anti- A N ACGAAGCAGCCACCAGGGCC
TGCGAGAGATTTGGCGATTTTTGGAGTGGTCCCCGACTACT
<huGIPR> ACTGGTATCCCAGCCAGGTTC
GGGGCCAGGGAACCCTGGTCACCGTGTCTAGTGCCTCCACC
2G10.610 AGTGGCAGTGGGTCTGGGAC
AAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAG
VH3 (1-472) AGAGTTCACTCTCACCATCAG
CACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGG 1-3
VH]::huIgG1 CAGCCTGCAGTCTGAAGATTT
ACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGC
oe
zSEFL2-2 TGCAGTTTATTACTGTCAGCA
GCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACA
(mAb); LMR GTATAACAACTGGCCTCTCAC
GTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGC
ID: SS- TTTCGGCGGAGGGACCAAGGT
CCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTG
26195 GGAGATCAAACGAACGGTGG
AATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTG oe
oe
113
A-2164-WO-PCT
CTGCACCATCTGTCTTCATCTT AGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGC
CCCGCCATCTGATGAGCAGTT CCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTC
GAAATCTGGAACTGCCTCTGT CCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCC
TGTGTGCCTGCTGAATAACTT TGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACC
CTATCCCAGAGAGGCCAAAG CTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTG
TACAGTGGAAGGTGGATAAC CATAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCA
GCCCTCCAATCGGGTAACTCC GCACGTACCGTTGCGTCAGCGTCCTCACCGTCCTGCACCAG
CAGGAGAGTGTCACAGAGCA GACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCCA
GGACAGCAAGGACAGCACCT ACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAA
ACAGCCTCAGCAGCACCCTGA GCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCC
CGCTGAGCAAAGCAGACTAC CCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTG
GAGAAACACAAAGTCTACGC ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGT
CTGCGAAGTCACCCATCAGGG GGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAG
CCTGAGCTCGCCCGTCACAAA ACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTC
GAGCTTCAACAGGGGAGAGT TATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGG
GT
GGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCAC
AACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAA
A
(SEQ ID NO: 44) (SEQ ID NO: 45)
EIVMTQSPATLSVSPGERATLS QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMHWVRQAP
CRASQSVLSHLAWYQQKPGQA GEGLEWVAAIWFDASDKYYADAVKGRFTISRDNSKNTLYLQ
PRLLIYEAATRATGIPARFSGSG MNSLRAEDTAVYYCARDLAIFGVVPDYWGQGTLVTVSSASTK
SGTEFTLTISSLQSEDFAVYYCQ GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALT
QYNNWPLTFGGGTKVEIKRTV SGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN
AA AAPSVFIFPPSDEQLKSGTASVV TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
CLLNNFYPREAKVQWKVDNAL MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCE
QSGNSQESVTEQDSKDSTYSLS EQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI
STLTLSKADYEKHKVYACEVT SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV
HQGLSSPVTKSFNRGEC
EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN
VFSCSVMHEALHNHYTQKSLSLSPGK
(SEQ ID NO: 46) (SEQ ID NO: 47)
1-3
[hu anti- GAAATAGTGATGACGCAGTCT
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCC
<huGIPR> CCAGCCACCCTGTCTGTGTCT
TGGGAGGTCCCTGAGACTCTCCTGTGCAGCATCTGGATTCA
re)
2G10.324 NA CCAGGGGAAAGAGCCACCCT
CCTTCAGTAACTATGGCATGCACTGGGTCCGCCAGGCTCCA
VK3 (1-236) CTCCTGCAGGGCCAGTCAGAG
GGCGAGGGGCTGGAGTGGGTGGCAGCTATATGGTTTGATGC
VL]::huKLC TGTTCTGAGTCACTTAGCCTG
AAGTGATAAATACTATGCAGACGCCGTGAAGGGCCGATTCA oe
oe
114
A-2164-WO-PCT
-CL + GTACCAGCAGAAACCTGGCC
CCATCTCCAGAGACAACTCCAAGAACACGCTGTATCTGCAA
[Unknown AGGCTCCCAGGCTCCTCATCT
ATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTG
anti- ACGAAGCAGCCACCAGGGCC
TGCGAGAGATTTGGCGATTTTTGGAGTGGTCCCCGACTACT
<huGIPR> ACTGGTATCCCAGCCAGGTTC
GGGGCCAGGGAACCCTGGTCACCGTGTCTAGTGCCTCCACC
2G10.610 AGTGGCAGTGGGTCTGGGAC
AAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAG
VH3 (1-472) AGAGTTCACTCTCACCATCAG
CACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGG
VH]::huIgG1 CAGCCTGCAGTCTGAAGATTT
ACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGC
zSEFL2-2 TGCAGTTTATTACTGTCAGCA
GCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACA
(mAb); LMR GTATCAGAACTGGCCTCTCAC
GTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGC
ID: SS- TTTCGGCGGAGGGACCAAGGT
CCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTG
26201 GGAGATCAAACGAACGGTGG
AATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTG
CTGCACCATCTGTCTTCATCTT AGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGC
CCCGCCATCTGATGAGCAGTT CCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTC
GAAATCTGGAACTGCCTCTGT CCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCC
TGTGTGCCTGCTGAATAACTT TGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACC
CTATCCCAGAGAGGCCAAAG CTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTG
TACAGTGGAAGGTGGATAAC CATAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCA
GCCCTCCAATCGGGTAACTCC GCACGTACCGTTGCGTCAGCGTCCTCACCGTCCTGCACCAG
CAGGAGAGTGTCACAGAGCA GACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCCA
GGACAGCAAGGACAGCACCT ACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAA
ACAGCCTCAGCAGCACCCTGA GCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCC
CGCTGAGCAAAGCAGACTAC CCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTG
GAGAAACACAAAGTCTACGC ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGT
CTGCGAAGTCACCCATCAGGG GGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAG
CCTGAGCTCGCCCGTCACAAA ACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTC
GAGCTTCAACAGGGGAGAGT TATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGG
GT
GGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCAC
AACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAA
A
(SEQ ID NO: 48) (SEQ ID NO: 49)
EIVMTQSPATLSVSPGERATLS QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMHWVRQAP
1-3
CRASQSVLSHLAWYQQKPGQA GEGLEWVAAIWFDASDKYYADAVKGRFTISRDNSKNTLYLQ
AA PRLLIYEAATRATGIPARFSGSG MNSLRAEDTAVYYCARDLAIFGVVPDYWGQGTLVTVSSASTK
SGTEFTLTISSLQSEDFAVYYCQ GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALT
oe
QYQNWPLTFGGGTKVEIKRTV SGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN
AAPSVFIFPPSDEQLKSGTASVV TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
oe
oe
115
A-2164-WO-PCT
CLLNNFYPREAKVQWKVDNAL MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCE
QSGNSQESVTEQDSKDSTYSLS EQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI
STLTLSKADYEKHKVYACEVT SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV
HQGLSSPVTKSFNRGEC
EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN
VFSCSVMHEALHNHYTQKSLSLSPGK
(SEQ ID NO: 50) (SEQ ID NO: 51)
GAAATAGTGATGACGCAGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCC
CCAGCCACCCTGTCTGTGTCT TGGGAGGTCCCTGAGACTCTCCTGTGCAGCATCTGGATTCA
CCAGGGGAAAGAGCCACCCT CCTTCAGTAACTATGGCATGCACTGGGTCCGCCAGGCTCCA
CTCCTGCAGGGCCAGTCAGAG GGCGAGGGGCTGGAGTGGGTGGCAGCTATATGGTTTGATGC
TGTTATGAGTCACTTAGCCTG AAGTGATAAATACTATGCAGACGCCGTGAAGGGCCGATTCA
GTACCAGCAGAAACCTGGCC CCATCTCCAGAGACAACTCCAAGAACACGCTGTATCTGCAA
AGGCTCCCAGGCTCCTCATCT ATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTG
[hu anti- ACGAAGCAGCCACCAGGGCC
TGCGAGAGATTTGGCGATTTTTGGAGTGGTCCCCGACTACT
<huGIPR> ACTGGTATCCCAGCCAGGTTC
GGGGCCAGGGAACCCTGGTCACCGTGTCTAGTGCCTCCACC
2G10.322 AGTGGCAGTGGGTCTGGGAC
AAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAG
VK3 (1-236) AGAGTTCACTCTCACCATCAG
CACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGG
VL]::huKLC CAGCCTGCAGTCTGAAGATTT
ACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGC
-CL + TGCAGTTTATTACTGTCAGCA
GCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACA
[Unknown GTATCAGAACTGGCCTCTCAC
GTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGC
anti- TTTCGGCGGAGGGACCAAGGT
CCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTG
NA
<huGIPR> GGAGATCAAACGAACGGTGG
AATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTG
2G10.610 CTGCACCATCTGTCTTCATCTT
AGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGC
VH3 (1-472) CCCGCCATCTGATGAGCAGTT
CCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTC
VH]::huIgG1 GAAATCTGGAACTGCCTCTGT
CCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCC
zSEFL2-2 TGTGTGCCTGCTGAATAACTT
TGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACC
(mAb); LMR CTATCCCAGAGAGGCCAAAG
CTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTG
ID: SS- TACAGTGGAAGGTGGATAAC
CATAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCA
26199 GCCCTCCAATCGGGTAACTCC
GCACGTACCGTTGCGTCAGCGTCCTCACCGTCCTGCACCAG
CAGGAGAGTGTCACAGAGCA GACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCCA
GGACAGCAAGGACAGCACCT ACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAA
1-3
ACAGCCTCAGCAGCACCCTGA GCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCC
CGCTGAGCAAAGCAGACTAC CCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTG
GAGAAACACAAAGTCTACGC ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGT
oe
CTGCGAAGTCACCCATCAGGG GGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAG
CCTGAGCTCGCCCGTCACAAA ACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTC
oe
oe
116
A-2164-WO-PCT
GAGCTTCAACAGGGGAGAGT TATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGG
GT
GGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCAC
AACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAA
A
(SEQ ID NO: 52) (SEQ ID NO: 53)
oe
EIVMTQSPATL SVSPGERATLS QVQLVE SGGGVVQPGRSLRL SCAASGFTFSNYGMHWVRQAP
CRASQSVMSHLAWYQQKPGQ GEGLEWVAAIWFDASDKYYADAVKGRFTISRDNSKNTLYLQ
APRLLIYEAATRATGIPARFSGS MNSLRAEDTAVYYCARDLAIFGVVPDYWGQGTLVTVSSASTK
GS GTEFTLTI S SLQ SEDFAVYYC GP SVFPLAP S SKST S GGTAALGCLVKDYFPEPVTVSWN S GALT
QQYQNWPLTFGGGTKVEIKRT SGVHTFPAVLQSSGLY SLSSVVTVP SSSLGTQTYICNVNHKP SN
VAAPSVFIFPPSDEQLKSGTASV TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
AA
VCLLNNFYPREAKVQWKVDN MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCE
ALQSGNSQESVTEQD SKD STY S EQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI
L SSTLTL SKADYEKHKVYACE SKAKGQPREPQVYTLPP SREEMTKNQVSLTCLVKGFYP SDIAV
VTHQGLSSPVTKSFNRGEC EWE SNGQPENNYKTTPPVLD SD
GSFFLY SKLTVD KSRWQQ GN
VFSCSVMHEALHNHYTQKSLSLSPGK
(SEQ ID NO: 54) (SEQ ID NO: 55)
GAAATAGTGATGACGCAGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCC
CCAGCCACCCTGTCTGTGTCT TGGGAGGTCCCTGAGACTCTCCTGTGCAGCATCTGGATTCA
[hu anti-
CCAGGGGAAAGAGCCACCCT CCTTCAGTAACTATGGCATGCACTGGGTCCGCCAGGCTCCA
<huGIPR>
CTCCTGCAGGGCCAGTCAGAG GGCGAGGGGCTGGAGTGGGTGGCAGCTATATGGTTTGATGC
2G10.306
TGTTCTGACGCACTTAGCCTG AAGTGATAAATACTATGCAGACGCCGTGAAGGGCCGATTCA
VK3 (1-236)
GTACCAGCAGAAACCTGGCC CCATCTCCAGAGACAACTCCAAGAACACGCTGTATCTGCAA
VL]::huKLC
AGGCTCCCAGGCTCCTCATCT ATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTG
-CL +
ACGAAGCAGCCACCAGGGCC TGCGAGAGATTTGGCGATTTTTGGAGTGGTCCCCGACTACT
[Unknown
ACTGGTATCCCAGCCAGGTTC GGGGCCAGGGAACCCTGGTCACCGTGTCTAGTGCCTCCACC
anti-
NA AGTGGCAGTGGGTCTGGGAC AAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAG
<huGIPR>
AGAGTTCACTCTCACCATCAG CACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGG
2G10.610
CAGCCTGCAGTCTGAAGATTT ACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGC
VH3 (1-472)
VH huI TGCAGTTTATTACTGTCAGCA
GCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACA
]::gG1
SEF GTATCAGAACTGGCCTCTCAC
GTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGC 1-3
zL2-2
TTTCGGCGGAGGGACCAAGGT CCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTG
(mAb); LMR
GGAGATCAAACGAACGGTGG AATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTG
ID. SS-
. = CTGCACCATCTGTCTTCATCTT
AGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGC
oe
26192
CCCGCCATCTGATGAGCAGTT CCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTC
GAAATCTGGAACTGCCTCTGT CCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCC
oe
oe
117
A-2164-WO-PCT
TGTGTGCCTGCTGAATAACTT TGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACC
CTATCCCAGAGAGGCCAAAG CTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTG
TACAGTGGAAGGTGGATAAC CATAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCA
GCCCTCCAATCGGGTAACTCC GCACGTACCGTTGCGTCAGCGTCCTCACCGTCCTGCACCAG
CAGGAGAGTGTCACAGAGCA GACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCCA
GGACAGCAAGGACAGCACCT ACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAA
ACAGCCTCAGCAGCACCCTGA GCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCC
CGCTGAGCAAAGCAGACTAC CCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTG
GAGAAACACAAAGTCTACGC ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGT
CTGCGAAGTCACCCATCAGGG GGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAG
CCTGAGCTCGCCCGTCACAAA ACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTC
GAGCTTCAACAGGGGAGAGT TATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGG
GT
GGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCAC
AACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAA
A
(SEQ ID NO: 56) (SEQ ID NO: 57)
EIVMTQSPATL SVSPGERATLS QVQLVE SGGGVVQPGRSLRL SCAASGFTFSNYGMHWVRQAP
CRASQSVLTHLAWYQQKPGQA GEGLEWVAAIWFDASDKYYADAVKGRFTISRDNSKNTLYLQ
PRLLIYEAATRATGIPARFSGSG MNSLRAEDTAVYYCARDLAIFGVVPDYWGQGTLVTVSSASTK
SGTEFTLTISSLQSEDFAVYYCQ GP SVFPLAP S SKST S GGTAALGCLVKDYFPEPVTVSWN S GALT
QYQNWPLTFGGGTKVEIKRTV SGVHTFPAVLQSSGLY SLSSVVTVP SSSLGTQTYICNVNHKP SN
AA AAP SVFIFPP SDEQLKSGTASVV
TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
CLLNNFYPREAKVQWKVDNAL MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCE
QSGNSQESVTEQD SKD STY SL S EQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI
STLTLSKADYEKHKVYACEVT SKAKGQPREPQVYTLPP SREEMTKNQVSLTCLVKGFYP SDIAV
HQGL SSPVTKSFNRGEC EWE SNGQPENNYKTTPPVLD SD
GSFFLY SKLTVD KSRWQQ GN
VFSCSVMHEALHNHYTQKSLSLSPGK
(SEQ ID NO: 58) (SEQ ID NO: 59)
[hu anti- GAAATAGTGATGACGCAGTCT
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCC
<huGIPR> CCAGCCACCCTGTCTGTGTCT
TGGGAGGTCCCTGAGACTCTCCTGTGCAGCATCTGGATTCA
2G10.331 CCAGGGGAAAGAGCCACCCT
CCTTCAGTAACTATGGCATGCACTGGGTCCGCCAGGCTCCA 1-3
VK3 (1-236) NA CTCCTGCAGGGCCAGTCAGAG GGCGAGGGGCTGGAGTGGGTGGCAGCTATATGGTTTGATGC
VL]::huKLC TGTTGATCTGCACTTAGCCTG
AAGTGATAAATACTATGCAGACGCCGTGAAGGGCCGATTCA
-CL + GTACCAGCAGAAACCTGGCC
CCATCTCCAGAGACAACTCCAAGAACACGCTGTATCTGCAA
oe
[Unknown AGGCTCCCAGGCTCCTCATCT
ATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTG
" anti- ACGAAGCAGCCACCAGGGCC
TGCGAGAGATTTGGCGATTTTTGGAGTGGTCCCCGACTACT oe
oe
118
A-2164-WO-PCT
<huGIPR> ACTGGTATCCCAGCCAGGTTC
GGGGCCAGGGAACCCTGGTCACCGTGTCTAGTGCCTCCACC
2G10.610 AGTGGCAGTGGGTCTGGGAC
AAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAG
VH3 (1-472) AGAGTTCACTCTCACCATCAG
CACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGG
VH]::huIgG1 CAGCCTGCAGTCTGAAGATTT
ACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGC
zSEFL2-2 TGCAGTTTATTACTGTCAGCA
GCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACA
(mAb); LMR GTATCAGAACTGGCCTCTCAC
GTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGC
ID: SS- TTTCGGCGGAGGGACCAAGGT
CCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTG
26208 GGAGATCAAACGAACGGTGG
AATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTG
CTGCACCATCTGTCTTCATCTT AGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGC
CCCGCCATCTGATGAGCAGTT CCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTC
GAAATCTGGAACTGCCTCTGT CCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCC
TGTGTGCCTGCTGAATAACTT TGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACC
CTATCCCAGAGAGGCCAAAG CTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTG
TACAGTGGAAGGTGGATAAC CATAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCA
GCCCTCCAATCGGGTAACTCC GCACGTACCGTTGCGTCAGCGTCCTCACCGTCCTGCACCAG
CAGGAGAGTGTCACAGAGCA GACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCCA
GGACAGCAAGGACAGCACCT ACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAA
ACAGCCTCAGCAGCACCCTGA GCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCC
CGCTGAGCAAAGCAGACTAC CCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTG
GAGAAACACAAAGTCTACGC ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGT
CTGCGAAGTCACCCATCAGGG GGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAG
CCTGAGCTCGCCCGTCACAAA ACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTC
GAGCTTCAACAGGGGAGAGT TATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGG
GT
GGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCAC
AACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAA
A
(SEQ ID NO: 60) (SEQ ID NO: 61)
EIVMTQ SP ATL SVSPGERATLS QVQLVE SGGGVVQPGRSLRL SCAA S GFTF SNYGMHWVRQ AP
CRASQSVDLHLAWYQQKPGQ GEGLEWVAAIWFDASDKYYADAVKGRFTISRDNSKNTLYLQ
APRLLIYEAATRATGIPARFSGS MNSLRAEDTAVYYCARDLAIFGVVPDYWGQGTLVTVSSASTK
GS GTEFTL TI S SLQSEDFAVYYC GP SVFPL AP S SKST S GGT AALGCL VKDYFPEPVTVSWN S
GAL T
1-3
AA QQYQNWPLTFGGGTKVEIKRT SGVHTFPAVLQS SGLY SLS SVVTVP S S
SLGTQTYICNVNHKP SN
VAAPSVFIFPPSDEQLKSGTASV TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
VCLLNNFYPREAKVQWKVDN MI SRTPEVTCVVVDVSHEDPEVKFNWYVD GVEVHNAKTKPCE
oe
ALQSGNSQESVTEQD SKD STY S EQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI
L SSTLTL SKADYEKHKVYACE SKAKGQPREPQVYTLPP SREEMTKNQVSLTCLVKGFYP SDIAV
oe
oe
119
A-2164-WO-PCT
VTHQGLSSPVTKSFNRGEC
EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN
VFSCSVMHEALHNHYTQKSLSLSPGK
(SEQ ID NO: 62) (SEQ ID NO: 63)
0
GAAATAGTGATGACGCAGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCC
CCAGCCACCCTGTCTGTGTCT TGGGAGGTCCCTGAGACTCTCCTGTGCAGCATCTGGATTCA
oe
CCAGGGGAAAGAGCCACCCT CCTTCAGTAACTATGGCATGCACTGGGTCCGCCAGGCTCCA
CTCCTGCAGGGCCAGTCAGAG GGCGAGGGGCTGGAGTGGGTGGCAGCTATATGGTTTGATGC
TGTTAGCGAACACTTAGCCTG AAGTGATAAATACTATGCAGACGCCGTGAAGGGCCGATTCA
GTACCAGCAGAAACCTGGCC CCATCTCCAGAGACAACTCCAAGAACACGCTGTATCTGCAA
AGGCTCCCAGGCTCCTCATCT ATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTG
ACGAAGCAGCCACCAGGGCC TGCGAGAGATCTGGCGATTTTTGGAGTGATTCCCGACTACT
ACTGGTATCCCAGCCAGGTTC GGGGCCAGGGAACCCTGGTCACCGTGTCTAGTGCCTCCACC
[hu anti- AGTGGCAGTGGGTCTGGGAC
AAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAG
<huGIPR> AGAGTTCACTCTCACCATCAG
CACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGG
2G10.320 CAGCCTGCAGTCTGAAGATTT
ACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGC
VK3 (1-236) TGCAGTTTATTACTGTCAGCA
GCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACA p
VL]::huKLC GTATCAGAACTGGCCTCTCAC
GTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGC
-CL + [hu TTTCGGCGGAGGGACCAAGGT
CCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTG
anti- GGAGATCAAACGAACGGTGG
AATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTG
<huGIPR> NA CTGCACCATCTGTCTTCATCTT
AGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGC
2G10.320 CCCGCCATCTGATGAGCAGTT
CCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTC
VH3 (1-472) GAAATCTGGAACTGCCTCTGT
CCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCC
VH]::huIgG1 TGTGTGCCTGCTGAATAACTT
TGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACC
zSEFL2-2 CTATCCCAGAGAGGCCAAAG
CTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTG
(mAb); LMR TACAGTGGAAGGTGGATAAC
CATAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCA
ID: SS- GCCCTCCAATCGGGTAACTCC
GCACGTACCGTTGCGTCAGCGTCCTCACCGTCCTGCACCAG
26197 CAGGAGAGTGTCACAGAGCA
GACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCCA
GGACAGCAAGGACAGCACCT ACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAA
ACAGCCTCAGCAGCACCCTGA GCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCC
CGCTGAGCAAAGCAGACTAC CCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTG
GAGAAACACAAAGTCTACGC ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGT
1-3
CTGCGAAGTCACCCATCAGGG GGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAG
CCTGAGCTCGCCCGTCACAAA ACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTC
GAGCTTCAACAGGGGAGAGT TATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGG
oe
GT
GGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCAC
AACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAA
oe
cr
oe
120
A-2164-WO-PCT
A
(SEQ ID NO: 64) (SEQ ID NO: 65)
EIVMTQSPATLSVSPGERATLS QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMHWVRQAP
0
n.)
CRASQSVSEHLAWYQQKPGQA GEGLEWVAAIWFDASDKYYADAVKGRFTISRDNSKNTLYLQ
=
PRLLIYEAATRATGIPARFSGSG MNSLRAEDTAVYYCARDLAIFGVIPDYWGQGTLVTVSSASTK
oe
i-J
SGTEFTLTISSLQSEDFAVYYCQ GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALT
c,.)
--.1
QYQNWPLTFGGGTKVEIKRTV SGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN
o
AA AAPSVFIFPPSDEQLKSGTASVV TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
--.1
CLLNNFYPREAKVQWKVDNAL MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCE
QSGNSQESVTEQDSKDSTYSLS EQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI
STLTLSKADYEKHKVYACEVT SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV
HQGLSSPVTKSFNRGEC
EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN
VFSCSVMHEALHNHYTQKSLSLSPGK
(SEQ ID NO: 66) (SEQ ID NO: 67)
GAAATAGTGATGACGCAGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCC
CCAGCCACCCTGTCTGTGTCT TGGGAGGTCCCTGAGACTCTCCTGTGCAGCATCTGGATTCA
p
CCAGGGGAAAGAGCCACCCT CCTTCAGTAACTATGGCATGCACTGGGTCCGCCAGGCTCCA
[hu anti- CTCCTGCAGGGCCAGTCAGAG
GGCGAGGGGCTGGAGTGGGTGGCAGCTATATGGTTTGATGC .
,
<huGIPR> TGTTAGCGAACACTTAGCCTG
AAGTGATAAATACTATGCAGACGCCGTGAAGGGCCGATTCA .
2G10.320 GTACCAGCAGAAACCTGGCC
CCATCTCCAGAGACAACTCCAAGAACACGCTGTATCTGCAA
,
VK3 (1-236) AGGCTCCCAGGCTCCTCATCT
ATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTG .
,
,
VL]::huKLC ACGAAGCAGCCACCAGGGCC
TGCGAGAGATTTGGCGATTTTTGGAGTGGTCCCCGACTACT .
,
-CL + ACTGGTATCCCAGCCAGGTTC
GGGGCCAGGGAACCCTGGTCACCGTGTCTAGTGCCTCCACC ,
[Unknown AGTGGCAGTGGGTCTGGGAC
AAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAG
anti- NA AGAGTTCACTCTCACCATCAG
CACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGG
<huGIPR> CAGCCTGCAGTCTGAAGATTT
ACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGC
2G10.610 TGCAGTTTATTACTGTCAGCA
GCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACA
VH3 (1-472) GTATCAGAACTGGCCTCTCAC
GTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGC
VH]::huIgG1 TTTCGGCGGAGGGACCAAGGT
CCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTG
z5EFL2-2 GGAGATCAAACGAACGGTGG
AATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTG 00
n
(mAb); LMR CTGCACCATCTGTCTTCATCTT
AGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGC 1-3
ID: SS- CCCGCCATCTGATGAGCAGTT
CCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTC
cp
A 26205 GAAATCTGGAACTGCCTCTGT
CCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCC n.)
n
o
o TGTGTGCCTGCTGAATAACTT
TGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACC
oe
Pi CTATCCCAGAGAGGCCAAAG
CTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTG 'a
TACAGTGGAAGGTGGATAAC CATAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCA
oe
cr
oe
121
A-2164-WO-PCT
GCCCTCCAATCGGGTAACTCC GCACGTACCGTTGCGTCAGCGTCCTCACCGTCCTGCACCAG
CAGGAGAGTGTCACAGAGCA GACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCCA
GGACAGCAAGGACAGCACCT ACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAA
ACAGCCTCAGCAGCACCCTGA GCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCC
CGCTGAGCAAAGCAGACTAC CCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTG
GAGAAACACAAAGTCTACGC ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGT
CTGCGAAGTCACCCATCAGGG GGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAG
CCTGAGCTCGCCCGTCACAAA ACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTC
GAGCTTCAACAGGGGAGAGT TATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGG
GT
GGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCAC
AACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAA
A
(SEQ ID NO: 68) (SEQ ID NO: 69)
EIVMTQSPATLSVSPGERATLS QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMHWVRQAP
CRASQSVSEHLAWYQQKPGQA GEGLEWVAAIWFDASDKYYADAVKGRFTISRDNSKNTLYLQ
PRLLIYEAATRATGIPARFSGSG MNSLRAEDTAVYYCARDLAIFGVVPDYWGQGTLVTVSSASTK
SGTEFTLTISSLQSEDFAVYYCQ GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALT
QYQNWPLTFGGGTKVEIKRTV SGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN
AAPSVFIFPPSDEQLKSGTASVV TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
AA
CLLNNFYPREAKVQWKVDNAL MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCE
QSGNSQESVTEQDSKDSTYSLS EQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI
STLTLSKADYEKHKVYACEVT SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV
HQGLSSPVTKSFNRGEC
EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN
VFSCSVMHEALHNHYTQKSLSLSPGK
(SEQ ID NO: 70) (SEQ ID NO: 71)
[hu anti- GAAATAGTGATGACGCAGTCT
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCC
<huGIPR> CCAGCCACCCTGTCTGTGTCT
TGGGAGGTCCCTGAGACTCTCCTGTGCAGCATCTGGATTCA
2G10.333 CCAGGGGAAAGAGCCACCCT
CCTTCAGTAACTATGGCATGCACTGGGTCCGCCAGGCTCCA
VK3 (1-236) CTCCTGCAGGGCCAGTCAGAG
GGCGAGGGGCTGGAGTGGGTGGCAGCTATATGGTTTGATGC
VL]::huKLC TGTTAGCCGGCACTTAGCCTG
AAGTGATAAATACTATGCAGACGCCGTGAAGGGCCGATTCA
-CL + NA GTACCAGCAGAAACCTGGCC
CCATCTCCAGAGACAACTCCAAGAACACGCTGTATCTGCAA 1-
3
[Unknown AGGCTCCCAGGCTCCTCATCT
ATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTG
re) re) anti- ACGAAGCAGCCACCAGGGCC
TGCGAGAGATTTGGCGATTTTTGGAGTGGTCCCCGACTACT
re)
<huGIPR> ACTGGTATCCCAGCCAGGTTC
GGGGCCAGGGAACCCTGGTCACCGTGTCTAGTGCCTCCACC
2G10.610 AGTGGCAGTGGGTCTGGGAC
AAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAG
VH3 (1-472) AGAGTTCACTCTCACCATCAG
CACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGG oe
oe
122
A-2164-WO-PCT
VH]::huIgG1 CAGCCTGCAGTCTGAAGATTT
ACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGC
zSEFL2-2 TGCAGTTTATTACTGTCAGCA
GCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACA
(mAb); LMR GTATCAGCACTGGCCTCTCAC
GTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGC
ID: SS- TTTCGGCGGAGGGACCAAGGT
CCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTG
26210 GGAGATCAAACGAACGGTGG
AATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTG
CTGCACCATCTGTCTTCATCTT AGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGC
CCCGCCATCTGATGAGCAGTT CCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTC
GAAATCTGGAACTGCCTCTGT CCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCC
TGTGTGCCTGCTGAATAACTT TGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACC
CTATCCCAGAGAGGCCAAAG CTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTG
TACAGTGGAAGGTGGATAAC CATAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCA
GCCCTCCAATCGGGTAACTCC GCACGTACCGTTGCGTCAGCGTCCTCACCGTCCTGCACCAG
CAGGAGAGTGTCACAGAGCA GACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCCA
GGACAGCAAGGACAGCACCT ACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAA
ACAGCCTCAGCAGCACCCTGA GCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCC
CGCTGAGCAAAGCAGACTAC CCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTG
GAGAAACACAAAGTCTACGC ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGT
CTGCGAAGTCACCCATCAGGG GGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAG
CCTGAGCTCGCCCGTCACAAA ACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTC
GAGCTTCAACAGGGGAGAGT TATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGG
GT
GGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCAC
AACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAA
A
(SEQ ID NO: 72) (SEQ ID NO: 73)
EIVMTQSPATLSVSPGERATLS QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMHWVRQAP
CRASQSVSRHLAWYQQKPGQA GEGLEWVAAIWFDASDKYYADAVKGRFTISRDNSKNTLYLQ
PRLLIYEAATRATGIPARFSGSG MNSLRAEDTAVYYCARDLAIFGVVPDYWGQGTLVTVSSASTK
SGTEFTLTISSLQSEDFAVYYCQ GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALT
QYQHWPLTFGGGTKVEIKRTV SGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN
AA AAPSVFIFPPSDEQLKSGTASVV TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
CLLNNFYPREAKVQWKVDNAL MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCE
1-3
QSGNSQESVTEQDSKDSTYSLS EQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI
STLTLSKADYEKHKVYACEVT SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV
HQGLSSPVTKSFNRGEC
EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN
oe
VFSCSVMHEALHNHYTQKSLSLSPGK
(SEQ ID NO: 74) (SEQ ID NO: 75)
oe
oe
123
A-2164-WO-PCT
GAAATAGTGATGACGCAGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCC
CCAGCCACCCTGTCTGTGTCT TGGGAGGTCCCTGAGACTCTCCTGTGCAGCATCTGGATTCA
CCAGGGGAAAGAGCCACCCT CCTTCCAGAACTATGGCATGCACTGGGTCCGCCAGGCTCCA
0
CTCCTGCAGGGCCAGTCAGAG GGCGAGGGGCTGGAGTGGGTGGCAGCTATATGGTTTGATGC
o
TGTTTTCAGCCACTTAGCCTG GTCTGACAAATACTATGCAGACGCCGTGAAGGGCCGATTCA
oe
GTACCAGCAGAAACCTGGCC CCATCTCCAGAGACAACTCCAAGAACACGCTGTATCTGCAA
c,.)
-4
AGGCTCCCAGGCTCCTCATCT ATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTG
o
vo
ACGAAGCAGCCACCAGGGCC TGCGAGAGATCTTGCGATTTTTGGAGTGGTCCCCGACTACTG
-4
ACTGGTATCCCAGCCAGGTTC GGGCCAGGGAACCCTGGTCACCGTGTCTAGTGCCTCCACCA
AGTGGCAGTGGGTCTGGGAC AGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGC
AGAGTTCACTCTCACCATCAG ACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGA
[hu anti-
CAGCCTGCAGTCTGAAGATTT CTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCG
<huGIPR>
TGCAGTTTATTACTGTCAGCA CCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAG
2G10.301
GTATCAGAACTGGCCTCTCAC TCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCC
VK3 (1-236)
TTTCGGCGGAGGGACCAAGGT TCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAA
VL]::huKLC
GGAGATCAAACGAACGGTGG TCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAG
P
-CL + [hu
CTGCACCATCTGTCTTCATCTT CCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCC
o
anti- NA
,D
CCCGCCATCTGATGAGCAGTT AGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCC
.
<huGIPR>
,
GAAATCTGGAACTGCCTCTGT CCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTG
"
2G10.301
.
TGTGTGCCTGCTGAATAACTT AGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCT
"
,D
VH3 (1-472)
,
CTATCCCAGAGAGGCCAAAG GAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCA
' ,
VH]::huIgG1
,
TACAGTGGAAGGTGGATAAC TAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCAGC
,
zSEFL2-2
GCCCTCCAATCGGGTAACTCC ACGTACCGTTGCGTCAGCGTCCTCACCGTCCTGCACCAGGA
,
(mAb); LMR
CAGGAGAGTGTCACAGAGCA CTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCCAACA
ID: SS-
GGACAGCAAGGACAGCACCT AAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCC
26178
ACAGCCTCAGCAGCACCCTGA AAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCC
CGCTGAGCAAAGCAGACTAC ATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCT
GAGAAACACAAAGTCTACGC GCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAG
CTGCGAAGTCACCCATCAGGG TGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCA
CCTGAGCTCGCCCGTCACAAA CGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATA
00
GAGCTTCAACAGGGGAGAGT GCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAA
n
1-3
GT
CGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCA
,-
CTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA ___________________________ cp
o
n
o
o (SEQ ID NO: 76) (SEQ ID NO:
77)
oe
Pi AA EIVMTQSPATLSVSPGERATLS
QVQLVESGGGVVQPGRSLRLSCAASGFTFQNYGMHWVRQAP -1
CRASQSVFSHLAWYQQKPGQA GEGLEWVAAIWFDASDKYYADAVKGRFTISRDNSKNTLYLQ
oe
c:
oe
124
A-2164-W0- P CT
PRLLIYEAATRATGIPARFSGSG MNSLRAEDTAVYYCARDLAIFGVVPDYWGQGTLVTVSSASTK
SGTEFTLTISSLQSEDFAVYYCQ GP SVFPL AP S SKST S GGTAALGCLVKDYFPEPVTVSWN S GAL T
QYQNWPLTFGGGTKVEIKRTV SGVHTFPAVLQSSGLY SLSSVVTVP SSSLGTQTYICNVNHKP SN
AAP SVFIFPP SDEQLKSGTASVV TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
CLLNNFYPREAKVQWKVDNAL MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCE
QSGNSQESVTEQD SKD STY SL S EQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI
STLTLSKADYEKHKVYACEVT SKAKGQPREPQVYTLPP SREEMTKNQVSLTCLVKGFYP SDIAV
HQGL SSPVTKSFNRGEC
EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN
VFSCSVMHEALHNHYTQKSLSLSPGK
(SEQ ID NO: 78) (SEQ ID NO: 79)
GAAATAGTGATGACGCAGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCC
CCAGCCACCCTGTCTGTGTCT TGGGAGGTCCCTGAGACTCTCCTGTGCAGCATCTGGATTCA
CCAGGGGAAAGAGCCACCCT CCTTCCAGAACTATGGCATGCACTGGGTCCGCCAGGCTCCA
CTCCTGCAGGGCCAGTCAGAG GGCGAGGGGCTGGAGTGGGTGGCAGCTATATGGTTTGATGC
TGTTTTCAGCCACTTAGCCTG GTCTGACAAATACTATGCAGACGCCGTGAAGGGCCGATTCA
GTACCAGCAGAAACCTGGCC CCATCTCCAGAGACAACTCCAAGAACACGCTGTATCTGCAA
[hu anti-
AGGCTCCCAGGCTCCTCATCT ATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTG
<huGIPR>
ACGAAGCAGCCACCAGGGCC TGCGAGAGATCTTGCGATTTTTGGAGTGGTCCCCGACTACTG
2G10.601
ACTGGTATCCCAGCCAGGGTC GGGCCAGGGAACCCTGGTCACCGTGTCTAGTGCCTCCACCA
VK3 (1-236)
AGTGGCAGTGGGTCTGGGAC AGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGC
VL]::huKLC
AGAGTTCACTCTCACCATCAG ACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGA
-CL + [hu
CAGCCTGCAGTCTGAAGATTT CTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCG
anti-
TGCAGTTTATTACTGTCAGCA CCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAG
<huGIPR> NA
GTATCAGAACTGGCCTCTCAC TCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCC
2G10.301
VH3 1472)
TTTCGGCGGAGGGACCAAGGT TCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAA
(
VH GGAGATCAAACGAACGGTGG
TCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAG
] mIgG1 ::I
CTGCACCATCTGTCTTCATCTT CCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCC
zSEFL2-2
CCCGCCATCTGATGAGCAGTT AGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCC
(mAb); LMR
GAAATCTGGAACTGCCTCTGT CCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTG
ID: 26226 SS-
TGTGTGCCTGCTGAATAACTT AGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCT
CTATCCCAGAGAGGCCAAAG GAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCA
1-3
TACAGTGGAAGGTGGATAAC TAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCAGC
GCCCTCCAATCGGGTAACTCC ACGTACCGTTGCGTCAGCGTCCTCACCGTCCTGCACCAGGA
`z. CAGGAGAGTGTCACAGAGCA
CTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCCAACA
oe
GGACAGCAAGGACAGCACCT AAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCC
ACAGCCTCAGCAGCACCCTGA AAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCC
oe
oe
125
A-2164-WO-PCT
CGCTGAGCAAAGCAGACTAC ATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCT
GAGAAACACAAAGTCTACGC GCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAG
CTGCGAAGTCACCCATCAGGG TGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCA
CCTGAGCTCGCCCGTCACAAA CGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATA
GAGCTTCAACAGGGGAGAGT GCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAA
GT
CGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCA
CTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA
(SEQ ID NO: 80) (SEQ ID NO: 81)
EIVMTQ SP ATL SVSPGERATLS QVQLVE SGGGVVQPGRSLRL SCAASGFTFQNYGMHWVRQAP
CRASQSVFSHLAWYQQKPGQA GEGLEWVAAIWFDASDKYYADAVKGRFTISRDNSKNTLYLQ
PRLLIYEAATRATGIPARVSGSG MNSLRAEDTAVYYCARDLAIFGVVPDYWGQGTLVTVSSASTK
SGTEFTLTISSLQSEDFAVYYCQ GP SVFPL AP S SKST S GGTAALGCLVKDYFPEPVTVSWN S GAL T
QYQNWPLTFGGGTKVEIKRTV SGVHTFPAVLQSSGLY SLSSVVTVP SSSLGTQTYICNVNHKP SN
AAP SVFIFPP SDEQLKSGTASVV TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
AA
CLLNNFYPREAKVQWKVDNAL MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCE
QSGNSQESVTEQD SKD STY SL S EQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI
STLTLSKADYEKHKVYACEVT SKAKGQPREPQVYTLPP SREEMTKNQVSLTCLVKGFYP SDIAV
HQGL SSPVTKSFNRGEC
EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN
VFSCSVMHEALHNHYTQKSLSLSPGK
(SEQ ID NO: 82) (SEQ ID NO: 83)
h GAAATAGTGATGACGCAGTCT
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCC
[u anti-
CCAGCCACCCTGTCTGTGTCT TGGGAGGTCCCTGAGACTCTCCTGTGCAGCATCTGGATTCA
<huGIPR>
CCAGGGGAAAGAGCCACCCT CCTTCCAGAACTATGGCATGCACTGGGTCCGCCAGGCTCCA
2G10.326
VK3 1236)
CTCCTGCAGGGCCAGTCAGAG GGCGAGGGGCTGGAGTGGGTGGCAGCTATATGGTTTGATGC
(-
TGTTCTGAGTCACTTAGCCTG GTCTGACAAATACTATGCAGACGCCGTGAAGGGCCGATTCA
VL]::huKLC
GTACCAGCAGAAACCTGGCC CCATCTCCAGAGACAACTCCAAGAACACGCTGTATCTGCAA
-CL + [hu
AGGCTCCCAGGCTCCTCATCT ATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTG
anti-
ACGAAGCAGCCACCAGGGCC TGCGAGAGATCTTGCGATTTTTGGAGTGGTCCCCGACTACTG
<huGIPR> NA
ACTGGTATCCCAGCCAGGTTC GGGCCAGGGAACCCTGGTCACCGTGTCTAGTGCCTCCACCA
2G10.301
VH3 1 472)
AGTGGCAGTGGGTCTGGGAC AGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGC
(
AGAGTTCACTCTCACCATCAG ACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGA
1-3
VH]: -
:huIgG1
CAGCCTGCAGTCTGAAGATTT CTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCG
zSEFL=2-2
TGCAGTTTATTACTGTCAGCA CCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAG
cr'n! (mAb); LMR
GTATCAGCAGTGGCCTCTCAC TCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCC
It' ID: SS-
oe
TTTCGGCGGAGGGACCAAGGT TCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAA
==.?1 26203
GGAGATCAAACGAACGGTGG TCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAG
oe
oe
126
A-2164-WO-PCT
CTGCACCATCTGTCTTCATCTT CCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCC
CCCGCCATCTGATGAGCAGTT AGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCC
GAAATCTGGAACTGCCTCTGT CCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTG
TGTGTGCCTGCTGAATAACTT AGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCT
CTATCCCAGAGAGGCCAAAG GAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCA
TACAGTGGAAGGTGGATAAC TAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCAGC
GCCCTCCAATCGGGTAACTCC ACGTACCGTTGCGTCAGCGTCCTCACCGTCCTGCACCAGGA
CAGGAGAGTGTCACAGAGCA CTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCCAACA
GGACAGCAAGGACAGCACCT AAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCC
ACAGCCTCAGCAGCACCCTGA AAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCC
CGCTGAGCAAAGCAGACTAC ATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCT
GAGAAACACAAAGTCTACGC GCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAG
CTGCGAAGTCACCCATCAGGG TGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCA
CCTGAGCTCGCCCGTCACAAA CGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATA
GAGCTTCAACAGGGGAGAGT GCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAA
GT
CGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCA
CTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA
(SEQ ID NO: 84) (SEQ ID NO: 85)
EIVMTQSPATLSVSPGERATLS QVQLVESGGGVVQPGRSLRLSCAASGFTFQNYGMHWVRQAP
CRASQSVLSHLAWYQQKPGQA GEGLEWVAAIWFDASDKYYADAVKGRFTISRDNSKNTLYLQ
PRLLIYEAATRATGIPARFSGSG MNSLRAEDTAVYYCARDLAIFGVVPDYWGQGTLVTVSSASTK
SGTEFTLTISSLQSEDFAVYYCQ GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALT
QYQQWPLTFGGGTKVEIKRTV SGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN
AAPSVFIFPPSDEQLKSGTASVV TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
AA
CLLNNFYPREAKVQWKVDNAL MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCE
QSGNSQESVTEQDSKDSTYSLS EQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI
STLTLSKADYEKHKVYACEVT SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV
HQGLSSPVTKSFNRGEC
EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN
VFSCSVMHEALHNHYTQKSLSLSPGK
(SEQ ID NO: 86) (SEQ ID NO: 87)
[hu anti- GAAATAGTGATGACGCAGTCT
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCC 1-3
<huGIPR> CCAGCCACCCTGTCTGTGTCT
TGGGAGGTCCCTGAGACTCTCCTGTGCAGCATCTGGATTCA
2G10.308 A CCAGGGGAAAGAGCCACCCT
CCTTCAGTAACTATGGCATGCACTGGGTCCGCCAGGCTCCA
N re)
VK3 (1-236) CTCCTGCAGGGCCAGTCAGAG
GGCGAGGGGCTGGAGTGGGTGGCAGCTATATGGTTTGATGC
VL]::huKLC TGTTTTCAGCCACTTAGCCTG
AAGTGATAAATACTATGCAGACGCCGTGAAGGGCCGATTCA
-CL + GTACCAGCAGAAACCTGGCC
CCATCTCCAGAGACAACTCCAAGAACACGCTGTATCTGCAA oe
oe
127
A-2164-WO-PCT
[Unknown AGGCTCCCAGGCTCCTCATCT
ATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTG
anti- ACGAAGCAGCCACCAGGGCC
TGCGAGAGATTTGGCGATTTTTGGAGTGGTCCCCGACTACT
<huGIPR> ACTGGTATCCCAGCCAGGTTC
GGGGCCAGGGAACCCTGGTCACCGTGTCTAGTGCCTCCACC
2G10.610 AGTGGCAGTGGGTCTGGGAC
AAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAG
VH3 (1-472) AGAGTTCACTCTCACCATCAG
CACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGG
VH]::huIgG1 CAGCCTGCAGTCTGAAGATTT
ACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGC
zSEFL2-2 TGCAGTTTATTACTGTCAGCA
GCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACA
(mAb); LMR GTATCAGCAGTGGCCTCTCAC
GTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGC
ID: SS- TTTCGGCGGAGGGACCAAGGT
CCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTG
26185 GGAGATCAAACGAACGGTGG
AATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTG
CTGCACCATCTGTCTTCATCTT AGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGC
CCCGCCATCTGATGAGCAGTT CCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTC
GAAATCTGGAACTGCCTCTGT CCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCC
TGTGTGCCTGCTGAATAACTT TGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACC
CTATCCCAGAGAGGCCAAAG CTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTG
TACAGTGGAAGGTGGATAAC CATAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCA
GCCCTCCAATCGGGTAACTCC GCACGTACCGTTGCGTCAGCGTCCTCACCGTCCTGCACCAG
CAGGAGAGTGTCACAGAGCA GACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCCA
GGACAGCAAGGACAGCACCT ACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAA
ACAGCCTCAGCAGCACCCTGA GCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCC
CGCTGAGCAAAGCAGACTAC CCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTG
GAGAAACACAAAGTCTACGC ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGT
CTGCGAAGTCACCCATCAGGG GGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAG
CCTGAGCTCGCCCGTCACAAA ACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTC
GAGCTTCAACAGGGGAGAGT TATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGG
GT
GGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCAC
AACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAA
A
(SEQ ID NO: 88) (SEQ ID NO: 89)
EIVMTQ SP ATL SVSPGERATLS QVQLVE SGGGVVQPGRSLRL SCAA S GFTF SNYGMHWVRQ AP
CRASQSVFSHLAWYQQKPGQA GEGLEWVAAIWFDASDKYYADAVKGRFTISRDNSKNTLYLQ
1-3
PRLLIYEAATRATGIPARFSGSG MNSLRAEDTAVYYCARDLAIFGVVPDYWGQGTLVTVSSASTK
AA SGTEFTLTIS SLQSEDFAVYYCQ GP SVFPL AP S SKST S GGT AALGCL
VKDYFPEPVTVSWN S GAL T
QYQQWPLTFGGGTKVEIKRTV SGVHTFPAVLQS SGLY SLS SVVTVP S S SLGTQTYICNVNHKP SN
oe
AAP SVFIFPP SDEQLKSGTASVV TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
CLLNNFYPREAKVQWKVDNAL MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCE
oe
oe
128
A-2164-WO-PCT
QSGNSQESVTEQDSKDSTYSLS EQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI
STLTLSKADYEKHKVYACEVT SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV
HQGLSSPVTKSFNRGEC
EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN
VFSCSVMHEALHNHYTQKSLSLSPGK
(SEQ ID NO: 90) (SEQ ID NO: 91)
oe
GAAATAGTGATGACGCAGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCC
CCAGCCACCCTGTCTGTGTCT TGGGAGGTCCCTGAGACTCTCCTGTGCAGCATCTGGATTCA
CCAGGGGAAAGAGCCACCCT CCTTCAGTAACTATGGCATGCACTGGGTCCGCCAGGCTCCA
CTCCTGCAGGGCCAGTCAGAG GGCGAGGGGCTGGAGTGGGTGGCAGCTATATGGTTTGATGC
TGTTTTCAGCCACTTAGCCTG AAGTGATAAATACTATGCAGACGCCGTGAAGGGCCGATTCA
GTACCAGCAGAAACCTGGCC CCATCTCCAGAGACAACTCCAAGAACACGCTGTATCTGCAA
AGGCTCCCAGGCTCCTCATCT ATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTG
ACGAAGCAGCCACCAGGGCC TGCGAGAGATTTGGCGATTTTTGGAGTGGTCCCCGACTACT
[hu anti-
ACTGGTATCCCAGCCAGGGTC GGGGCCAGGGAACCCTGGTCACCGTGTCTAGTGCCTCCACC
<huGIPR>
AGTGGCAGTGGGTCTGGGAC AAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAG
2G10.608
VK3 1 236)
AGAGTTCACTCTCACCATCAG CACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGG
- (
CAGCCTGCAGTCTGAAGATTT ACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGC
VL]::huKLC
TGCAGTTTATTACTGTCAGCA GCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACA
-CL +
GTATCAGCAGTGGCCTCTCAC GTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGC
[Unknown
TTTCGGCGGAGGGACCAAGGT CCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTG
anti-
NA GGAGATCAAACGAACGGTGG AATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTG
<huGIPR>
CTGCACCATCTGTCTTCATCTT AGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGC
2G10.610
CCCGCCATCTGATGAGCAGTT CCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTC
VH3
::huIgG1 (1-472)
GAAATCTGGAACTGCCTCTGT CCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCC
VH]
SEF TGTGTGCCTGCTGAATAACTT
TGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACC
zL2-2
CTATCCCAGAGAGGCCAAAG CTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTG
(mAb); LMR
TACAGTGGAAGGTGGATAAC CATAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCA
ID: SS-
GCCCTCCAATCGGGTAACTCC GCACGTACCGTTGCGTCAGCGTCCTCACCGTCCTGCACCAG
26233
CAGGAGAGTGTCACAGAGCA GACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCCA
GGACAGCAAGGACAGCACCT ACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAA
ACAGCCTCAGCAGCACCCTGA GCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCC
CGCTGAGCAAAGCAGACTAC CCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTG
ci)
GAGAAACACAAAGTCTACGC ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGT
`z. CTGCGAAGTCACCCATCAGGG
GGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAG
CCTGAGCTCGCCCGTCACAAA ACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTC
GAGCTTCAACAGGGGAGAGT TATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGG
cr
129
A-2164-WO-PCT
GT
GGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCAC
AACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAA
A
(SEQ ID NO: 92) (SEQ ID NO: 93)
EIVMTQSPATL SVSPGERATLS QVQLVE SGGGVVQPGRSLRL SCAASGFTFSNYGMHWVRQAP
oe
CRASQSVFSHLAWYQQKPGQA GEGLEWVAAIWFDASDKYYADAVKGRFTISRDNSKNTLYLQ
PRLLIYEAATRATGIPARVSGSG MNSLRAEDTAVYYCARDLAIFGVVPDYWGQGTLVTVSSASTK
SGTEFTLTISSLQSEDFAVYYCQ GP SVFPL AP S SKST S GGTAALGCLVKDYFPEPVTVSWN S GAL T
QYQQWPLTFGGGTKVEIKRTV SGVHTFPAVLQSSGLY SLSSVVTVP SSSLGTQTYICNVNHKP SN
AA AAP SVFIFPP SDEQLKSGTASVV
TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
CLLNNFYPREAKVQWKVDNAL MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCE
QSGNSQESVTEQD SKD STY SL S EQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI
STLTLSKADYEKHKVYACEVT SKAKGQPREPQVYTLPP SREEMTKNQVSLTCLVKGFYP SDIAV
HQGL SSPVTKSFNRGEC
EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN
VFSCSVMHEALHNHYTQKSLSLSPGK
(SEQ ID NO: 94) (SEQ ID NO: 95)
p
GAAATAGTGATGACGCAGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCC
CCAGCCACCCTGTCTGTGTCT TGGGAGGTCCCTGAGACTCTCCTGTGCAGCATCTGGATTCA
CCAGGGGAAAGAGCCACCCT CCTTCAGTAACTATGGCATGCACTGGGTCCGCCAGGCTCCA
[hu anti-
GIPR> CTCCTGCAGGGCCAGTCAGAG
GGCGAGGGGCTGGAGTGGGTGGCAGCTATATGGTTTGATGC
<hu
TGTTCAGAGCCACTTAGCCTG AAGTGATAAATACTATGCAGACGCCGTGAAGGGCCGATTCA
2G10.336
GTACCAGCAGAAACCTGGCC CCATCTCCAGAGACAACTCCAAGAACACGCTGTATCTGCAA
VK3 (1-236)
AGGCTCCCAGGCTCCTCATCT ATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTG
VL]::huKLC
ACGAAGCAGCCACCAGGGCC TGCGAGAGATATTGCGATTTTTGGAGTGGTCCCCGACTACT
-CL + [hu
ACTGGTATCCCAGCCAGGTTC GGGGCCAGGGAACCCTGGTCACCGTGTCTAGTGCCTCCACC
NA
anti-
AGTGGCAGTGGGTCTGGGAC AAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAG
<huGIPR>
2G10.325 AGAGTTCACTCTCACCATCAG
CACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGG
CAGCCTGCAGTCTGAAGATTT ACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGC
VH3 (1-472)
TGCAGTTTATTACTGTCAGCA GCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACA
VH]::huIgG1
SEF GTATCAGAACTGGCCTCTCAC GTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGC
L2-2
z
TTTCGGCGGAGGGACCAAGGT CCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTG
1-3
(m b), LMR
GGAGATCAAACGAACGGTGG AATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTG
,z ID: SS-
re)
f 1 26213 CTGCACCATCTGTCTTCATCTT AGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGC
CCCGCCATCTGATGAGCAGTT CCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTC
oe
GAAATCTGGAACTGCCTCTGT CCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCC
TGTGTGCCTGCTGAATAACTT TGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACC
oe
cr
oe
130
A-2164-WO-PCT
CTATCCCAGAGAGGCCAAAG CTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTG
TACAGTGGAAGGTGGATAAC CATAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCA
GCCCTCCAATCGGGTAACTCC GCACGTACCGTTGCGTCAGCGTCCTCACCGTCCTGCACCAG
CAGGAGAGTGTCACAGAGCA GACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCCA
GGACAGCAAGGACAGCACCT ACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAA
ACAGCCTCAGCAGCACCCTGA GCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCC
CGCTGAGCAAAGCAGACTAC CCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTG
GAGAAACACAAAGTCTACGC ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGT
CTGCGAAGTCACCCATCAGGG GGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAG
CCTGAGCTCGCCCGTCACAAA ACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTC
GAGCTTCAACAGGGGAGAGT TATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGG
GT
GGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCAC
AACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAA
A
(SEQ ID NO: 96) (SEQ ID NO: 97)
EIVMTQSPATL SVSPGERATLS QVQLVE SGGGVVQPGRSLRL SCAASGFTFSNYGMHWVRQAP
CRASQSVQSHLAWYQQKPGQ GEGLEWVAAIWFDASDKYYADAVKGRFTISRDNSKNTLYLQ
APRLLIYEAATRATGIPARFSGS MNSLRAEDTAVYYCARDIAIFGVVPDYWGQGTLVTVSSASTK
GS GTEFTLTI S SLQ SEDFAVYYC GP SVFPLAP S SKST S GGTAALGCLVKDYFPEPVTVSWN S GALT
QQYQNWPLTFGGGTKVEIKRT SGVHTFPAVLQSSGLY SLSSVVTVP SSSLGTQTYICNVNHKP SN
VAAPSVFIFPPSDEQLKSGTASV TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
AA
VCLLNNFYPREAKVQWKVDN MI SRTPEVTCVVVDVSHEDPEVKFNWYVD GVEVHNAKTKPCE
ALQSGNSQESVTEQD SKD STY S EQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI
L SSTLTL SKADYEKHKVYACE SKAKGQPREPQVYTLPP SREEMTKNQVSLTCLVKGFYP SDIAV
VTHQGLSSPVTKSFNRGEC EWE SNGQPENNYKTTPPVLD SD
GSFFLY SKLTVD KSRWQQ GN
VFSCSVMHEALHNHYTQKSLSLSPGK
(SEQ ID NO: 98) (SEQ ID NO: 99)
[hu anti- GAAATAGTGATGACGCAGTCT
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCC
<huGIPR> CCAGCCACCCTGTCTGTGTCT
TGGGAGGTCCCTGAGACTCTCCTGTGCAGCATCTGGATTCA
2G10.344 CCAGGGGAAAGAGCCACCCT
CCTTCAGTAACTATGGCATGCACTGGGTCCGCCAGGCTCCA
VK3 (1-236) CTCCTGCAGGGCCAGTCAGAG
GGCGAGGGGCTGGAGTGGGTGGCAGCTATATGGTTTGATGC 1-3
VL]::huKLC NA TGTTAGTAGCCACTTAGCCTG AAGTGATAAATACTATGCAGACGCCGTGAAGGGCCGATTCA
-CL + [hu GTACCAGCAGAAACCTGGCC
CCATCTCCAGAGACAACTCCAAGAACACGCTGTATCTGCAA
g anti- AGGCTCCCAGGCTCCTCATCT
ATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTG
<huGIPR> ACGAAGCAGCCACCAGGGCC
TGCGAGAGATATTGCGATTTTTGGAGTGGTCCCCGACTACT
2G10.325 ACTGGTATCCCAGCCAGGTTC
GGGGCCAGGGAACCCTGGTCACCGTGTCTAGTGCCTCCACC oe
oe
131
A-2164-WO-PCT
VH3 (1-472) AGTGGCAGTGGGTCTGGGAC
AAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAG
VH]::huIgG1 AGAGTTCACTCTCACCATCAG
CACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGG
zSEFL2-2 CAGCCTGCAGTCTGAAGATTT
ACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGC
(mAb); LMR TGCAGTTTATTACTGTCAGCA
GCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACA
ID: SS- GTATCAGCAGTGGCCTCTCAC
GTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGC
26221 TTTCGGCGGAGGGACCAAGGT
CCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTG
GGAGATCAAACGAACGGTGG AATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTG
CTGCACCATCTGTCTTCATCTT AGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGC
CCCGCCATCTGATGAGCAGTT CCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTC
GAAATCTGGAACTGCCTCTGT CCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCC
TGTGTGCCTGCTGAATAACTT TGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACC
CTATCCCAGAGAGGCCAAAG CTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTG
TACAGTGGAAGGTGGATAAC CATAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCA
GCCCTCCAATCGGGTAACTCC GCACGTACCGTTGCGTCAGCGTCCTCACCGTCCTGCACCAG
CAGGAGAGTGTCACAGAGCA GACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCCA
GGACAGCAAGGACAGCACCT ACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAA
ACAGCCTCAGCAGCACCCTGA GCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCC
CGCTGAGCAAAGCAGACTAC CCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTG
GAGAAACACAAAGTCTACGC ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGT
CTGCGAAGTCACCCATCAGGG GGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAG
CCTGAGCTCGCCCGTCACAAA ACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTC
GAGCTTCAACAGGGGAGAGT TATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGG
GT
GGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCAC
AACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAA
A
(SEQ ID NO: 100) (SEQ ID NO: 101)
EIVMTQSPATLSVSPGERATLS QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMHWVRQAP
CRASQSVSSHLAWYQQKPGQA GEGLEWVAAIWFDASDKYYADAVKGRFTISRDNSKNTLYLQ
PRLLIYEAATRATGIPARFSGSG MNSLRAEDTAVYYCARDIAIFGVVPDYWGQGTLVTVSSASTK
SGTEFTLTISSLQSEDFAVYYCQ GP SVFPLAP SSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALT
AA
QYQQWPLTFGGGTKVEIKRTV SGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN
1-3
AAP SVFIFPP SDEQLKSGTASVV TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
CLLNNFYPREAKVQWKVDNAL MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCE
QSGNSQESVTEQDSKDSTYSLS EQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI
oe
STLTLSKADYEKHKVYACEVT SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV
HQGLSSPVTKSFNRGEC
EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN oe
oe
132
A-2164-WO-PCT
VFSCSVMHEALHNHYTQKSLSLSPGK
(SEQ ID NO: 102) (SEQ ID NO: 103)
GAAATAGTGATGACGCAGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCC
CCAGCCACCCTGTCTGTGTCT TGGGAGGTCCCTGAGACTCTCCTGTGCAGCATCTGGATTCA
CCAGGGGAAAGAGCCACCCT CCTTCAGTAACTATGGCATGCACTGGGTCCGCCAGGCTCCA
oe
CTCCTGCAGGGCCAGTCAGAG GGCGAGGGGCTGGAGTGGGTGGCAGCTATATGGTTTGATGC
TGTTTTCACGCACTTAGCCTG AAGTGATAAATACTATGCAGACGCCGTGAAGGGCCGATTCA
GTACCAGCAGAAACCTGGCC CCATCTCCAGAGACAACTCCAAGAACACGCTGTATCTGCAA
AGGCTCCCAGGCTCCTCATCT ATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTG
ACGAAGCAGCCACCAGGGCC TGCGAGAGATTTGGCGATTTTTGGAGTGGTCCCCGACTACT
ACTGGTATCCCAGCCAGGTTC GGGGCCAGGGAACCCTGGTCACCGTGTCTAGTGCCTCCACC
[hu anti- AGTGGCAGTGGGTCTGGGAC
AAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAG
<huGIPR> AGAGTTCACTCTCACCATCAG
CACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGG
2G10.310 CAGCCTGCAGTCTGAAGATTT
ACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGC
VK3 (1-236) TGCAGTTTATTACTGTCAGCA
GCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACA
VL]::huKLC GTATAACAACTGGCCTCTCAC
GTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGC
-CL + TTTCGGCGGAGGGACCAAGGT
CCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTG
[Unknown GGAGATCAAACGAACGGTGG
AATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTG
anti- CTGCACCATCTGTCTTCATCTT
AGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGC
<huGIPR> NACCCGCCATCTGATGAGCAGTT CCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTC
2G10.610 GAAATCTGGAACTGCCTCTGT
CCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCC
VH3 (1-472) TGTGTGCCTGCTGAATAACTT
TGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACC
VH]::huIgG1 CTATCCCAGAGAGGCCAAAG
CTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTG
zSEFL2-2 TACAGTGGAAGGTGGATAAC
CATAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCA
(mAb); LMR GCCCTCCAATCGGGTAACTCC
GCACGTACCGTTGCGTCAGCGTCCTCACCGTCCTGCACCAG
ID: SS- CAGGAGAGTGTCACAGAGCA
GACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCCA
26187 GGACAGCAAGGACAGCACCT
ACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAA
ACAGCCTCAGCAGCACCCTGA GCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCC
CGCTGAGCAAAGCAGACTAC CCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTG
GAGAAACACAAAGTCTACGC ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGT
CTGCGAAGTCACCCATCAGGG GGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAG
1-3
CCTGAGCTCGCCCGTCACAAA ACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTC
GAGCTTCAACAGGGGAGAGT TATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGG
GT
GGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCAC
oe
AACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAA
A
oe
cr
oe
133
A-2164-W0- P CT
(SEQ ID NO: 104) (SEQ ID NO: 105)
EIVMTQ SP ATL SVSPGERATLS QVQLVE SGGGVVQPGRSLRL SCAASGFTFSNYGMHWVRQAP
CRASQSVFTHLAWYQQKPGQA GEGLEWVAAIWFDASDKYYADAVKGRFTISRDNSKNTLYLQ
PRLLIYEAATRATGIPARFSGSG MNSLRAEDTAVYYCARDLAIFGVVPDYWGQGTLVTVSSASTK
SGTEFTLTIS SLQSEDFAVYYCQ GP SVFPL AP S SKST S GGTAALGCL VKDYFPEPVTVSWN S GAL T
oe
QYNNWPLTFGGGTKVEIKRTV SGVHTFPAVLQS SGLY SLS SVVTVP S S SLGTQTYICNVNHKP SN
AAP SVFIFPP SDEQLKSGTASVV TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
AA
CLLNNFYPREAKVQWKVDNAL MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCE
QSGNSQESVTEQD SKD STY SL S EQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI
STLTLSKADYEKHKVYACEVT SKAKGQPREPQVYTLPP SREEMTKNQVSLTCLVKGFYP SDIAV
HQGL S SPVTKSFNRGEC EWE SNGQPENNYKTTPPVLD SD
GSFFLY SKL TVD KSRWQQ GN
VFSCSVMHEALHNHYTQKSLSLSPGK
(SEQ ID NO: 106) (SEQ ID NO: 107)
GAAATAGTGATGACGCAGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCC
CCAGCCACCCTGTCTGTGTCT TGGGAGGTCCCTGAGACTCTCCTGTGCAGCATCTGGATTCA
CCAGGGGAAAGAGCCACCCT CCTTCAGTAACTATGGCATGCACTGGGTCCGCCAGGCTCCA
p
[Unknown CTCCTGCAGGGCCAGTCAGAG
GGCGAGGGGCTGGAGTGGGTGGCAGCTATATGGTTTGATGC
anti- TGTTTTCACGCACTTAGCCTG
AAGTGATAAATACTATGCAGACGCCGTGAAGGGCCGATTCA
<huGIPR> GTACCAGCAGAAACCTGGCC
CCATCTCCAGAGACAACTCCAAGAACACGCTGTATCTGCAA
2G10.610 AGGCTCCCAGGCTCCTCATCT
ATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTG
VK3 (1-236) ACGAAGCAGCCACCAGGGCC
TGCGAGAGATTTGGCGATTTTTGGAGTGGTCCCCGACTACT
VL]::huKLC ACTGGTATCCCAGCCAGGGTC
GGGGCCAGGGAACCCTGGTCACCGTGTCTAGTGCCTCCACC
-CL + AGTGGCAGTGGGTCTGGGAC
AAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAG
[Unknown AGAGTTCACTCTCACCATCAG
CACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGG
anti- NA CAGCCTGCAGTCTGAAGATTT
ACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGC
<huGIPR> TGCAGTTTATTACTGTCAGCA
GCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACA
2G10.610 GTATAACAACTGGCCTCTCAC
GTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGC
VH3 (1-472) TTTCGGCGGAGGGACCAAGGT
CCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTG
VH]::huIgG1 GGAGATCAAACGAACGGTGG
AATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTG
zSEFL2-2 CTGCACCATCTGTCTTCATCTT
AGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGC
(mAb); LMR CCCGCCATCTGATGAGCAGTT
CCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTC
1-3
ID: SS- GAAATCTGGAACTGCCTCTGT
CCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCC
26235 TGTGTGCCTGCTGAATAACTT
TGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACC
`z.
CTATCCCAGAGAGGCCAAAG CTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTG
oe
TACAGTGGAAGGTGGATAAC CATAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCA
GCCCTCCAATCGGGTAACTCC GCACGTACCGTTGCGTCAGCGTCCTCACCGTCCTGCACCAG
oe
oe
134
A-2164-WO-PCT
CAGGAGAGTGTCACAGAGCA GACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCCA
GGACAGCAAGGACAGCACCT ACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAA
ACAGCCTCAGCAGCACCCTGA GCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCC
CGCTGAGCAAAGCAGACTAC CCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTG
GAGAAACACAAAGTCTACGC ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGT
CTGCGAAGTCACCCATCAGGG GGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAG
CCTGAGCTCGCCCGTCACAAA ACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTC
GAGCTTCAACAGGGGAGAGT TATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGG
GT
GGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCAC
AACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAA
A
(SEQ ID NO: 108) (SEQ ID NO: 109)
EIVMTQ SP ATL SVSPGERATLS QVQLVE SGGGVVQPGRSLRL SCAA S GFTF SNYGMHWVRQ AP
CRASQSVFTHLAWYQQKPGQA GEGLEWVAAIWFDASDKYYADAVKGRFTISRDNSKNTLYLQ
PRLLIYEAATRATGIPARVSGSG MNSLRAEDTAVYYCARDLAIFGVVPDYWGQGTLVTVSSASTK
SGTEFTLTIS SLQSEDFAVYYCQ GP SVFPL AP S SKST S GGT AALGCL VKDYFPEPVTVSWN S GAL
T
QYNNWPLTFGGGTKVEIKRTV SGVHTFPAVLQS SGLY SLS SVVTVP S S SLGTQTYICNVNHKP SN
AA AAP SVFIFPP SDEQLKSGTASVV
TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
CLLNNFYPREAKVQWKVDNAL MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCE
QSGNSQESVTEQD SKD STY SL S EQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI
STLTLSKADYEKHKVYACEVT SKAKGQPREPQVYTLPP SREEMTKNQVSLTCLVKGFYP SDIAV
HQGL S SPVTKSFNRGEC EWE SNGQPENNYKTTPPVLD SD
GSFFLY SKL TVD KSRWQQ GN
VFSCSVMHEALHNHYTQKSLSLSPGK
(SEQ ID NO: 110) (SEQ ID NO: 111)
[hu anti- GAAATAGTGATGACGCAGTCT
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCC
<huGIPR> CCAGCCACCCTGTCTGTGTCT
TGGGAGGTCCCTGAGACTCTCCTGTGCAGCATCTGGATTCA
2G10.302 CCAGGGGAAAGAGCCACCCT
CCTTCAGTAACTATGGCATGCACTGGGTCCGCCAGGCTCCA
VK3 (1-236) CTCCTGCAGGGCCAGTCAGAG
GGCGAGGGGCTGGAGTGGGTGGCAGCTATATGGTTTGATGC
VL]::huKLC TGTTTTTGAACACTTAGCCTG
AAGTGATAAATACTATGCAGACGCCGTGAAGGGCCGATTCA
-CL + NA GTACCAGCAGAAACCTGGCC
CCATCTCCAGAGACAACTCCAAGAACACGCTGTATCTGCAA
[Unknown AGGCTCCCAGGCTCCTCATCT
ATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTG 1-3
anti- ACGAAGCAGCCACCAGGGCC
TGCGAGAGATTTGGCGATTTTTGGAGTGGTCCCCGACTACT
<huGIPR> ACTGGTATCCCAGCCAGGTTC
GGGGCCAGGGAACCCTGGTCACCGTGTCTAGTGCCTCCACC
re)
2G10.610 AGTGGCAGTGGGTCTGGGAC
AAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAG
VH3 (1-472) AGAGTTCACTCTCACCATCAG
CACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGG
VH]::huIgG1 CAGCCTGCAGTCTGAAGATTT
ACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGC oe
oe
135
A-2164-WO-PCT
zSEFL2-2 TGCAGTTTATTACTGTCAGCA
GCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACA
(mAb); LMR GTATAACAACTGGCCTCTCAC
GTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGC
ID: SS- TTTCGGCGGAGGGACCAAGGT
CCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTG
26189 GGAGATCAAACGAACGGTGG
AATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTG
CTGCACCATCTGTCTTCATCTT AGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGC
CCCGCCATCTGATGAGCAGTT CCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTC
GAAATCTGGAACTGCCTCTGT CCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCC
TGTGTGCCTGCTGAATAACTT TGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACC
CTATCCCAGAGAGGCCAAAG CTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTG
TACAGTGGAAGGTGGATAAC CATAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCA
GCCCTCCAATCGGGTAACTCC GCACGTACCGTTGCGTCAGCGTCCTCACCGTCCTGCACCAG
CAGGAGAGTGTCACAGAGCA GACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCCA
GGACAGCAAGGACAGCACCT ACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAA
ACAGCCTCAGCAGCACCCTGA GCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCC
CGCTGAGCAAAGCAGACTAC CCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTG
GAGAAACACAAAGTCTACGC ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGT
CTGCGAAGTCACCCATCAGGG GGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAG
CCTGAGCTCGCCCGTCACAAA ACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTC
GAGCTTCAACAGGGGAGAGT TATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGG
GT
GGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCAC
AACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAA
A
(SEQ ID NO: 112) (SEQ ID NO: 113)
EIVMTQSPATLSVSPGERATLS QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMHWVRQAP
CRASQSVFEHLAWYQQKPGQA GEGLEWVAAIWFDASDKYYADAVKGRFTISRDNSKNTLYLQ
PRLLIYEAATRATGIPARFSGSG MNSLRAEDTAVYYCARDLAIFGVVPDYWGQGTLVTVSSASTK
SGTEFTLTISSLQSEDFAVYYCQ GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALT
QYNNWPLTFGGGTKVEIKRTV SGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN
AA AAPSVFIFPPSDEQLKSGTASVV TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
CLLNNFYPREAKVQWKVDNAL MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCE
QSGNSQESVTEQDSKDSTYSLS EQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI
1-3
STLTLSKADYEKHKVYACEVT SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV
HQGLSSPVTKSFNRGEC
EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN
VFSCSVMHEALHNHYTQKSLSLSPGK
oe
(SEQ ID NO: 114) (SEQ ID NO: 115)
" [hu anti- NA GAAATAGTGATGACGCAGTCT
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCC oe
oe
136
A-2164-WO-PCT
<huGIPR> CCAGCCACCCTGTCTGTGTCT
TGGGAGGTCCCTGAGACTCTCCTGTGCAGCATCTGGATTCA
2G10.329 CCAGGGGAAAGAGCCACCCT
CCTTCAGTAACTATGGCATGCACTGGGTCCGCCAGGCTCCA
VK3 (1-236) CTCCTGCAGGGCCAGTCAGAG
GGCGAGGGGCTGGAGTGGGTGGCAGCTATATGGTTTGATGC
VL]::huKLC TGTTGAACAGCACTTAGCCTG
AAGTGATAAATACTATGCAGACGCCGTGAAGGGCCGATTCA
-CL + GTACCAGCAGAAACCTGGCC
CCATCTCCAGAGACAACTCCAAGAACACGCTGTATCTGCAA
[Unknown AGGCTCCCAGGCTCCTCATCT
ATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTG
anti- ACGAAGCAGCCACCAGGGCC
TGCGAGAGATTTGGCGATTTTTGGAGTGGTCCCCGACTACT
<huGIPR> ACTGGTATCCCAGCCAGGTTC
GGGGCCAGGGAACCCTGGTCACCGTGTCTAGTGCCTCCACC
2G10.610 AGTGGCAGTGGGTCTGGGAC
AAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAG
VH3 (1-472) AGAGTTCACTCTCACCATCAG
CACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGG
VH]::huIgG1 CAGCCTGCAGTCTGAAGATTT
ACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGC
zSEFL2-2 TGCAGTTTATTACTGTCAGCA
GCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACA
(mAb); LMR GTATAACAACTGGCCTCTCAC
GTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGC
ID: SS- TTTCGGCGGAGGGACCAAGGT
CCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTG
26206 GGAGATCAAACGAACGGTGG
AATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTG
CTGCACCATCTGTCTTCATCTT AGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGC
CCCGCCATCTGATGAGCAGTT CCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTC
GAAATCTGGAACTGCCTCTGT CCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCC
TGTGTGCCTGCTGAATAACTT TGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACC
CTATCCCAGAGAGGCCAAAG CTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTG
TACAGTGGAAGGTGGATAAC CATAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCA
GCCCTCCAATCGGGTAACTCC GCACGTACCGTTGCGTCAGCGTCCTCACCGTCCTGCACCAG
CAGGAGAGTGTCACAGAGCA GACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCCA
GGACAGCAAGGACAGCACCT ACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAA
ACAGCCTCAGCAGCACCCTGA GCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCC
CGCTGAGCAAAGCAGACTAC CCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTG
GAGAAACACAAAGTCTACGC ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGT
CTGCGAAGTCACCCATCAGGG GGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAG
CCTGAGCTCGCCCGTCACAAA ACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTC
GAGCTTCAACAGGGGAGAGT TATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGG
GT
GGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCAC
1-3
AACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAA
A
(SEQ ID NO: 116) (SEQ ID NO: 117)
oe
AA EIVMTQ SP ATL SVSPGERATLS QVQLVE SGGGVVQPGRSLRL SCAA S
GFTF SNYGMHWVRQ AP
CRASQSVEQHLAWYQQKPGQ GEGLEWVAAIWFDASDKYYADAVKGRFTISRDNSKNTLYLQ
oe
oe
137
A-2164-WO-PCT
APRLLIYEAATRATGIPARFSGS MNSLRAEDTAVYYCARDLAIFGVVPDYWGQGTLVTVSSASTK
GSGTEFTLTISSLQSEDFAVYYC GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALT
QQYNNWPLTFGGGTKVEIKRT SGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN
VAAPSVFIFPPSDEQLKSGTASV TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
VCLLNNFYPREAKVQWKVDN MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCE
ALQSGNSQESVTEQDSKDSTYS EQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI
LSSTLTLSKADYEKHKVYACE SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV
VTHQGLSSPVTKSFNRGEC
EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN
VFSCSVMHEALHNHYTQKSLSLSPGK
(SEQ ID NO: 118) (SEQ ID NO: 119)
GAAATAGTGATGACGCAGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCC
CCGGCCACCCTGTCTGTGTCT TGGGAGGTCCCTGAGACTCTCCTGTGCAGCATCTGGATTCA
CCAGGGGAAAGAGCCACCCT CCTTCAGTAACTATGGCATGCACTGGGTCCGCCAGGCTCCA
CTCCTGCAGGGCCAGTCAGAG GGCGAGGGGCTGGAGTGGGTGGCAGCTATATGGTTTGATGC
TGTTCATAGCCACTTAGCCTG AAGTGATAAATACTATGCAGACGCCGTGAAGGGCCGATTCA
[hu anti- GTACCAGCAGAAACCTGGCC
CCATCTCCAGAGACAACTCCAAGAACACGCTGTATCTGCAA
<huGIPR> AGGCTCCCAGGCTCCTCATCT
ATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTG
2G10.327 ACGAAGCAGCCACCAGGGCC
TGCGAGAGATTTGGCGATTTTTGGAGTGGTCCCCGACTACT
VK3 (1-236) ACTGGTATCCCAGCCAGGTTC
GGGGCCAGGGAACCCTGGTCACCGTGTCTAGTGCCTCCACC
VL]::huKLC AGTGGCAGTGGGTCTGGGAC
AAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAG
-CL + AGAGTTCACTCTCACCATCAG
CACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGG
[Unknown CAGCCTGCAGTCTGAAGATTT
ACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGC
anti- A N TGCAGTTTATTACTGTCAGCA
GCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACA
<huGIPR> GTATAACCAGTGGCCTCTCAC
GTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGC
2G10.610 TTTCGGCGGAGGGACCAAGGT
CCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTG
VH3 (1-472) GGAGATCAAACGAACGGTGG
AATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTG
VH]::huIgG1 CTGCACCATCTGTCTTCATCTT
AGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGC
zSEFL2-2 CCCGCCATCTGATGAGCAGTT
CCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTC
(mAb); LMR GAAATCTGGAACTGCCTCTGT
CCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCC
ID: SS- TGTGTGCCTGCTGAATAACTT
TGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACC
26204 CTATCCCAGAGAGGCCAAAG
CTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTG
1-3
TACAGTGGAAGGTGGATAAC CATAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCA
GCCCTCCAATCGGGTAACTCC GCACGTACCGTTGCGTCAGCGTCCTCACCGTCCTGCACCAG
CAGGAGAGTGTCACAGAGCA GACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCCA
oe
GGACAGCAAGGACAGCACCT ACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAA
ACAGCCTCAGCAGCACCCTGA GCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCC
oe
oe
138
A-2164-WO-PCT
CGCTGAGCAAAGCAGACTAC CCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTG
GAGAAACACAAAGTCTACGC ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGT
CTGCGAAGTCACCCATCAGGG GGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAG
CCTGAGCTCGCCCGTCACAAA ACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTC
GAGCTTCAACAGGGGAGAGT TATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGG
GT
GGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCAC
AACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAA
A
(SEQ ID NO: 120) (SEQ ID NO: 121)
EIVMTQ SP ATL SVSPGERATLS QVQLVE SGGGVVQPGRSLRL SCAASGFTFSNYGMHWVRQAP
CRASQSVHSHLAWYQQKPGQ GEGLEWVAAIWFDASDKYYADAVKGRFTISRDNSKNTLYLQ
APRLLIYEAATRATGIPARFSGS MNSLRAEDTAVYYCARDLAIFGVVPDYWGQGTLVTVSSASTK
GS GTEFTL TI S SLQSEDFAVYYC GP SVFPL AP S SKST S GGT AALGCL VKDYFPEPVTVSWN S
GAL T
QQYNQWPLTFGGGTKVEIKRT SGVHTFPAVLQS SGLY SLS SVVTVP S S SLGTQTYICNVNHKP SN
AA VAAPSVFIFPPSDEQLKSGTASV TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
VCLLNNFYPREAKVQWKVDN MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCE
ALQSGNSQESVTEQDSKDSTYS EQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI
L SSTLTL SKADYEKHKVYACE SKAKGQPREPQVYTLPP SREEMTKNQVSLTCLVKGFYP SDIAV
VTHQGLSSPVTKSFNRGEC
EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN
VFSCSVMHEALHNHYTQKSLSLSPGK
(SEQ ID NO: 122) (SEQ ID NO: 123)
[hu anti- GAAATAGTGATGACGCAGTCT
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCC
<huGIPR> CCAGCCACCCTGTCTGTGTCT
TGGGAGGTCCCTGAGACTCTCCTGTGCAGCATCTGGATTCA
2G10.338 CCAGGGGAAAGAGCCACCCT
CCTTCAGTAACTATGGCATGCACTGGGTCCGCCAGGCTCCA
VK3 (1-236) CTCCTGCAGGGCCAGTCAGAG
GGCGAGGGGCTGGAGTGGGTGGCAGCTATATGGTTTGATGC
VL]::huKLC TGTTCATCATCACTTAGCCTG
AAGTGATAAATACTATGCAGACGCCGTGAAGGGCCGATTCA
-CL + GTACCAGCAGAAACCTGGCC
CCATCTCCAGAGACAACTCCAAGAACACGCTGTATCTGCAA
[Unknown AGGCTCCCAGGCTCCTCATCT
ATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTG
anti- NA ACGAAGCAGCCACCAGGGCC
TGCGAGAGATTTGGCGATTTTTGGAGTGGTCCCCGACTACT
<huGIPR> ACTGGTATCCCAGCCAGGTTC
GGGGCCAGGGAACCCTGGTCACCGTGTCTAGTGCCTCCACC
2G10.610 AGTGGCAGTGGGTCTGGGAC
AAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAG 1-3
VH3 (1-472) AGAGTTCACTCTCACCATCAG
CACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGG
VH]::huIgG1 CAGCCTGCAGTCTGAAGATTT
ACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGC
re)
Z SEFL2-2 TGCAGTTTATTACTGTCAGCA
GCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACA
(mAb); LMR GTATAACCAGTGGCCTCTCAC
GTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGC
ID: SS- TTTCGGCGGAGGGACCAAGGT
CCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTG oe
oe
139
A-2164-WO-PCT
26215 GGAGATCAAACGAACGGTGG
AATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTG
CTGCACCATCTGTCTTCATCTT AGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGC
CCCGCCATCTGATGAGCAGTT CCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTC
0
GAAATCTGGAACTGCCTCTGT CCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCC
n.)
o
TGTGTGCCTGCTGAATAACTT TGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACC
oe
i-J
CTATCCCAGAGAGGCCAAAG CTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTG
c,.)
--.1
TACAGTGGAAGGTGGATAAC CATAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCA
o
vo
GCCCTCCAATCGGGTAACTCC GCACGTACCGTTGCGTCAGCGTCCTCACCGTCCTGCACCAG
--.1
CAGGAGAGTGTCACAGAGCA GACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCCA
GGACAGCAAGGACAGCACCT ACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAA
ACAGCCTCAGCAGCACCCTGA GCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCC
CGCTGAGCAAAGCAGACTAC CCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTG
GAGAAACACAAAGTCTACGC ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGT
CTGCGAAGTCACCCATCAGGG GGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAG
CCTGAGCTCGCCCGTCACAAA ACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTC
GAGCTTCAACAGGGGAGAGT TATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGG
P
GT
GGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCAC o
AACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAA
.
,
A'.
(SEQ ID NO: 124) (SEQ ID NO: 125)
" EIVMTQSPATLSVSPGERATLS
QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMHWVRQAP y
,
CRASQSVHHHLAWYQQKPGQ GEGLEWVAAIWFDASDKYYADAVKGRFTISRDNSKNTLYLQ
.
,
APRLLIYEAATRATGIPARFSGS MNSLRAEDTAVYYCARDLAIFGVVPDYWGQGTLVTVSSASTK
,
GSGTEFTLTISSLQSEDFAVYYC GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALT
QQYNQWPLTFGGGTKVEIKRT SGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN
VAAPSVFIFPPSDEQLKSGTASV TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
AA
VCLLNNFYPREAKVQWKVDN MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCE
ALQSGNSQESVTEQDSKDSTYS EQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI
LSSTLTLSKADYEKHKVYACE SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV
VTHQGLSSPVTKSFNRGEC
EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN 00
VFSCSVMHEALHNHYTQKSLSLSPGK
n
1-3
(SEQ ID NO: 126) (SEQ ID NO: 127)
cp
,- [hu anti- GAAATAGTGATGACGCAGTCT
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCC n.)
o
re)
c> <huGIPR> NA CCAGCCACCCTGTCTGTGTCT TGGGAGGTCCCTGAGACTCTCCTGTGCAGCATCTGGATTCA
oe
2G10.314 CCAGGGGAAAGAGCCACCCT
CCTTCAGTAACTATGGCATGCACTGGGTCCGCCAGGCTCCA 'a
' VK3 (1-236) CTCCTGCAGGGCCAGTCAGAG
GGCGAGGGGCTGGAGTGGGTGGCAGCTATATGGTTTGATGC oe
c:
oe
140
A-2164-WO-P CT
VL]::huKLC TGTTCATAGCCACTTAGCCTG
AAGTGATAAATACTATGCAGACGCCGTGAAGGGCCGATTCA
-CL + GTACCAGCAGAAACCTGGCC
CCATCTCCAGAGACAACTCCAAGAACACGCTGTATCTGCAA
[Unknown AGGCTCCCAGGCTCCTCATCT
ATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTG
anti- ACGAAGCAGCCACCAGGGCC
TGCGAGAGATTTGGCGATTTTTGGAGTGGTCCCCGACTACT
<huGIPR> ACTGGTATCCCAGCCAGGTTC
GGGGCCAGGGAACCCTGGTCACCGTGTCTAGTGCCTCCACC
2G10.610 AGTGGCAGTGGGTCTGGGAC
AAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAG
VH3 (1-472) AGAGTTCACTCTCACCATCAG
CACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGG
VH]::huIgG1 CAGCCTGCAGTCTGAAGATTT
ACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGC
zSEFL2-2 TGCAGTTTATTACTGTCAGCA
GCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACA
(mAb); LMR GTATAACAACTGGCCTCTCAC
GTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGC
ID: SS- TTTCGGCGGAGGGACCAAGGT
CCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTG
26191 GGAGATCAAACGAACGGTGG
AATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTG
CTGCACCATCTGTCTTCATCTT AGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGC
CCCGCCATCTGATGAGCAGTT CCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTC
GAAATCTGGAACTGCCTCTGT CCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCC
TGTGTGCCTGCTGAATAACTT TGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACC
CTATCCCAGAGAGGCCAAAG CTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTG
TACAGTGGAAGGTGGATAAC CATAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCA
GCCCTCCAATCGGGTAACTCC GCACGTACCGTTGCGTCAGCGTCCTCACCGTCCTGCACCAG
CAGGAGAGTGTCACAGAGCA GACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCCA
GGACAGCAAGGACAGCACCT ACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAA
ACAGCCTCAGCAGCACCCTGA GCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCC
CGCTGAGCAAAGCAGACTAC CCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTG
GAGAAACACAAAGTCTACGC ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGT
CTGCGAAGTCACCCATCAGGG GGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAG
CCTGAGCTCGCCCGTCACAAA ACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTC
GAGCTTCAACAGGGGAGAGT TATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGG
GT
GGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCAC
AACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAA
A
(SEQ ID NO: 128) (SEQ ID NO: 129)
1-3
EIVMTQSPATLSVSPGERATLS QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMHWVRQAP
CRASQSVHSHLAWYQQKPGQ GEGLEWVAAIWFDASDKYYADAVKGRFTISRDNSKNTLYLQ
AA APRLLIYEAATRATGIPARFSGS MNSLRAEDTAVYYCARDLAIFGVVPDYWGQGTLVTVSSASTK
oe
GSGTEFTLTISSLQSEDFAVYYC GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALT
QQYNNWPLTFGGGTKVEIKRT SGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN
oe
oe
141
A-2164-WO-PCT
VAAPSVFIFPPSDEQLKSGTASV TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
VCLLNNFYPREAKVQWKVDN MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCE
ALQSGNSQESVTEQDSKDSTYS EQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI
LSSTLTLSKADYEKHKVYACE SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV
VTHQGLSSPVTKSFNRGEC
EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN
VFSCSVMHEALHNHYTQKSLSLSPGK
(SEQ ID NO: 130) (SEQ ID NO: 131)
GAAATAGTGATGACGCAGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCC
CCAGCCACCCTGTCTGTGTCT TGGGAGGTCCCTGAGACTCTCCTGTGCAGCATCTGGATTCA
CCAGGGGAAAGAGCCACCCT CCTTCAGTAACTATGGCATGCACTGGGTCCGCCAGGCTCCA
CTCCTGCAGGGCCAGTCAGAG GGCGAGGGGCTGGAGTGGGTGGCAGCTATATGGTTTGATGC
TGTTGATGTCAACTTAGCCTG AAGTGATAAATACTATGCAGACGCCGTGAAGGGCCGATTCA
GTACCAGCAGAAACCTGGCC CCATCTCCAGAGACAACTCCAAGAACACGCTGTATCTGCAA
h AGGCTCCCAGGCTCCTCATCT
ATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTG
R>
[u anti-
ACGAAGCAGCCACCAGGGCC TGCGAGAGATTTGGCGATTTTTGGAGTGGTCCCCGACTACT
<huGIP
2G10.337 ACTGGTATCCCAGCCAGGTTC
GGGGCCAGGGAACCCTGGTCACCGTGTCTAGTGCCTCCACC
VK3 1 236)
AGTGGCAGTGGGTCTGGGAC AAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAG
- (
AGAGTTCACTCTCACCATCAG CACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGG
VL]::huKLC
CAGCCTGCAGTCTGAAGATTT ACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGC
-CL +
TGCAGTTTATTACTGTCAGCA GCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACA
[Unknown
GTATAACCAGTGGCCTCTCAC GTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGC
anti-
NA TTTCGGCGGAGGGACCAAGGT CCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTG
<huGIPR>
GGAGATCAAACGAACGGTGG AATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTG
2G10.610
CTGCACCATCTGTCTTCATCTT AGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGC
VH3
::huIgG1 (1-472)
CCCGCCATCTGATGAGCAGTT CCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTC
VH]
SEFL2 GAAATCTGGAACTGCCTCTGT
CCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCC
z-2
TGTGTGCCTGCTGAATAACTT TGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACC
(mAb); LMR
CTATCCCAGAGAGGCCAAAG CTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTG
ID: SS-
TACAGTGGAAGGTGGATAAC CATAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCA
26214
GCCCTCCAATCGGGTAACTCC GCACGTACCGTTGCGTCAGCGTCCTCACCGTCCTGCACCAG
CAGGAGAGTGTCACAGAGCA GACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCCA
1-3
GGACAGCAAGGACAGCACCT ACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAA
ACAGCCTCAGCAGCACCCTGA GCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCC
CGCTGAGCAAAGCAGACTAC CCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTG
oe
GAGAAACACAAAGTCTACGC ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGT
CTGCGAAGTCACCCATCAGGG GGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAG
oe
oe
142
A-2164-WO-PCT
CCTGAGCTCGCCCGTCACAAA ACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTC
GAGCTTCAACAGGGGAGAGT TATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGG
GT
GGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCAC 0
AACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAA
n.)
o
A
oe
i-J
(SEQ ID NO: 132) (SEQ ID NO: 133)
c,.)
--.1
EIVMTQSPATLSVSPGERATLS QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMHWVRQAP
o
vo
CRASQSVDVNLAWYQQKPGQ GEGLEWVAAIWFDASDKYYADAVKGRFTISRDNSKNTLYLQ
--.1
APRLLIYEAATRATGIPARFSGS MNSLRAEDTAVYYCARDLAIFGVVPDYWGQGTLVTVSSASTK
GSGTEFTLTISSLQSEDFAVYYC GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALT
QQYNQWPLTFGGGTKVEIKRT SGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN
AA VAAPSVFIFPPSDEQLKSGTASV TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
VCLLNNFYPREAKVQWKVDN MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCE
ALQSGNSQESVTEQDSKDSTYS EQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI
LSSTLTLSKADYEKHKVYACE SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV
VTHQGLSSPVTKSFNRGEC
EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN P
VFSCSVMHEALHNHYTQKSLSLSPGK
.
(SEQ ID NO: 134) (SEQ ID NO: 135)
.
,
GAAATAGTGATGACGCAGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCC
.
[hu anti- CCAGCCACCCTGTCTGTGTCT
TGGGAGGTCCCTGAGACTCTCCTGTGCAGCATCTGGATTCA
,
<huGIPR> CCAGGGGAAAGAGCCACCCT
CCTTCAGTAACTATGGCATGCACTGGGTCCGCCAGGCTCCA
.
,
,
2G10.341 CTCCTGCAGGGCCAGTCAGAG
GGCGAGGGGCTGGAGTGGGTGGCAGCTATATGGTTTGATGC .
,
VK3 (1-236) TGTTGATGTCCACTTAGCCTG
AAGTGATAAATACTATGCAGACGCCGTGAAGGGCCGATTCA ,
VL]::huKLC GTACCAGCAGAAACCTGGCC
CCATCTCCAGAGACAACTCCAAGAACACGCTGTATCTGCAA
-CL + AGGCTCCCAGGCTCCTCATCT
ATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTG
[Unknown ACGAAGCAGCCACCAGGGCC
TGCGAGAGATTTGGCGATTTTTGGAGTGGTCCCCGACTACT
anti- NA ACTGGTATCCCAGCCAGGTTC
GGGGCCAGGGAACCCTGGTCACCGTGTCTAGTGCCTCCACC
<huGIPR> AGTGGCAGTGGGTCTGGGAC
AAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAG
2G10.610 AGAGTTCACTCTCACCATCAG
CACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGG
VH3 (1-472) CAGCCTGCAGTCTGAAGATTT
ACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGC 00
n
VH]::huIgG1 TGCAGTTTATTACTGTCAGCA
GCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACA 1-3
zSEFL2-2 GTATAACCAGTGGCCTCTCAC
GTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGC
cp
4 (mAb); LMR TTTCGGCGGAGGGACCAAGGT
CCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTG l=.)
re)
0
c5 ID: SS- GGAGATCAAACGAACGGTGG
AATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTG
26218 CTGCACCATCTGTCTTCATCTT
AGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGC 'a
CCCGCCATCTGATGAGCAGTT CCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTC
oe
c:
oe
143
A-2164-WO-PCT
GAAATCTGGAACTGCCTCTGT CCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCC
TGTGTGCCTGCTGAATAACTT TGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACC
CTATCCCAGAGAGGCCAAAG CTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTG
TACAGTGGAAGGTGGATAAC CATAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCA
GCCCTCCAATCGGGTAACTCC GCACGTACCGTTGCGTCAGCGTCCTCACCGTCCTGCACCAG
CAGGAGAGTGTCACAGAGCA GACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCCA
GGACAGCAAGGACAGCACCT ACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAA
ACAGCCTCAGCAGCACCCTGA GCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCC
CGCTGAGCAAAGCAGACTAC CCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTG
GAGAAACACAAAGTCTACGC ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGT
CTGCGAAGTCACCCATCAGGG GGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAG
CCTGAGCTCGCCCGTCACAAA ACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTC
GAGCTTCAACAGGGGAGAGT TATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGG
GT
GGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCAC
AACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAA
A
(SEQ ID NO: 136) (SEQ ID NO: 137)
EIVMTQ SP ATL SVSPGERATLS QVQLVE SGGGVVQPGRSLRL SCAASGFTFSNYGMHWVRQAP
CRASQSVDVHLAWYQQKPGQ GEGLEWVAAIWFDASDKYYADAVKGRFTISRDNSKNTLYLQ
APRLLIYEAATRATGIPARFSGS MNSLRAEDTAVYYCARDLAIFGVVPDYWGQGTLVTVSSASTK
GS GTEFTL TI S SLQSEDFAVYYC GP SVFPL AP S SKST S GGTAALGCLVKDYFPEPVTVSWN S GAL
T
QQYNQWPLTFGGGTKVEIKRT SGVHTFPAVLQS SGLY SLS SVVTVP S S SLGTQTYICNVNHKP SN
VAAPSVFIFPPSDEQLKSGTASV TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
AA
VCLLNNFYPREAKVQWKVDN MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCE
ALQSGNSQESVTEQD SKD STY S EQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI
L SSTLTL SKADYEKHKVYACE SKAKGQPREPQVYTLPP SREEMTKNQVSLTCLVKGFYP SDIAV
VTHQGLSSPVTKSFNRGEC EWE SNGQPENNYKTTPPVLD SD
GSFFLY SKL TVD KSRWQQ GN
VFSCSVMHEALHNHYTQKSLSLSPGK
(SEQ ID NO: 138) (SEQ ID NO: 139)
[hu anti- GAAATAGTGATGACGCAGTCT
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCC
<huGIPR> CCAGCCACCCTGTCTGTGTCT
TGGGAGGTCCCTGAGACTCTCCTGTGCAGCATCTGGATTCA 1-3
2G10.302 CCAGGGGAAAGAGCCACCCT
CCTTCAGTAACTATGGCATGCACTGGGTCCGCCAGGCTCCA
VK3 (1-236) NA CTCCTGCAGGGCCAGTCAGAG GGCGAGGGGCTGGAGTGGGTGGCAGCTATATGGTTTGATGC
re)
VL]::huKLC TGTTTTTGAACACTTAGCCTG
AAGTGATAAATACTATGCAGACGCCGTGAAGGGCCGATTCA
-CL + [hu GTACCAGCAGAAACCTGGCC
CCATCTCCAGAGACAACTCCAAGAACACGCTGTATCTGCAA
" anti- AGGCTCCCAGGCTCCTCATCT
ATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTG oe
oe
144
A-2164-WO-PCT
<huGIPR> ACGAAGCAGCCACCAGGGCC
TGCGAGAGATATTGCGATTTTTGGAGTGTTTCCCGACTACTG
2G10.302 ACTGGTATCCCAGCCAGGTTC
GGGCCAGGGAACCCTGGTCACCGTGTCTAGTGCCTCCACCA
VH3 (1-472) AGTGGCAGTGGGTCTGGGAC
AGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGC
VH]::huIgG1 AGAGTTCACTCTCACCATCAG
ACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGA
zSEFL2-2 CAGCCTGCAGTCTGAAGATTT
CTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCG
(mAb); LMR TGCAGTTTATTACTGTCAGCA
CCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAG
ID: SS- GTATAACAACTGGCCTCTCAC
TCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCC
26179 TTTCGGCGGAGGGACCAAGGT
TCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAA
GGAGATCAAACGAACGGTGG TCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAG
CTGCACCATCTGTCTTCATCTT CCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCC
CCCGCCATCTGATGAGCAGTT AGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCC
GAAATCTGGAACTGCCTCTGT CCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTG
TGTGTGCCTGCTGAATAACTT AGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCT
CTATCCCAGAGAGGCCAAAG GAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCA
TACAGTGGAAGGTGGATAAC TAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCAGC
GCCCTCCAATCGGGTAACTCC ACGTACCGTTGCGTCAGCGTCCTCACCGTCCTGCACCAGGA
CAGGAGAGTGTCACAGAGCA CTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCCAACA
GGACAGCAAGGACAGCACCT AAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCC
ACAGCCTCAGCAGCACCCTGA AAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCC
CGCTGAGCAAAGCAGACTAC ATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCT
GAGAAACACAAAGTCTACGC GCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAG
CTGCGAAGTCACCCATCAGGG TGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCA
CCTGAGCTCGCCCGTCACAAA CGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATA
GAGCTTCAACAGGGGAGAGT GCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAA
GT
CGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCA
CTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA
(SEQ ID NO: 140) (SEQ ID NO: 141)
EIVMTQ SP ATL SVSPGERATLS QVQLVE SGGGVVQPGRSLRL SCAA S GFTF SNYGMHWVRQ AP
CRASQSVFEHLAWYQQKPGQA GEGLEWVAAIWFDASDKYYADAVKGRFTISRDNSKNTLYLQ
PRLLIYEAATRATGIPARFSGSG MNSLRAEDTAVYYCARDIAIFGVFPDYWGQGTLVTVSSASTK
SGTEFTLTIS SLQSEDFAVYYCQ GP SVFPL AP S SKST S GGT AALGCL VKDYFPEPVTVSWN S GAL
T
1-3
AA QYNNWPLTFGGGTKVEIKRTV SGVHTFPAVLQS SGLY SLS SVVTVP S S
SLGTQTYICNVNHKP SN
AAP SVFIFPP SDEQLKSGTASVV TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
CLLNNFYPREAKVQWKVDNAL MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCE
oe
QSGNSQESVTEQD SKD STY SL S EQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI
STLTLSKADYEKHKVYACEVT SKAKGQPREPQVYTLPP SREEMTKNQVSLTCLVKGFYP SDIAV
oe
oe
145
A-2164-WO-PCT
HQGLSSPVTKSFNRGEC
EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN
VFSCSVMHEALHNHYTQKSLSLSPGK
(SEQ ID NO: 142) (SEQ ID NO: 143)
0
GAAATAGTGATGACGCAGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCC
CCAGCCACCCTGTCTGTGTCT TGGGAGGTCCCTGAGACTCTCCTGTGCAGCATCTGGATTCA
oe
CCAGGGGAAAGAGCCACCCT CCTTCAGTAACTATGGCATGCACTGGGTCCGCCAGGCTCCA
CTCCTGCAGGGCCAGTCAGAG GGCGAGGGGCTGGAGTGGGTGGCAGCTATATGGTTTGATGC
TGTTTTTGAACACTTAGCCTG AAGTGATAAATACTATGCAGACGCCGTGAAGGGCCGATTCA
GTACCAGCAGAAACCTGGCC CCATCTCCAGAGACAACTCCAAGAACACGCTGTATCTGCAA
AGGCTCCCAGGCTCCTCATCT ATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTG
ACGAAGCAGCCACCAGGGCC TGCGAGAGATATTGCGATTTTTGGAGTGTTTCCCGACTACTG
ACTGGTATCCCAGCCAGGGTC GGGCCAGGGAACCCTGGTCACCGTGTCTAGTGCCTCCACCA
[hu anti- AGTGGCAGTGGGTCTGGGAC
AGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGC
<huGIPR> AGAGTTCACTCTCACCATCAG
ACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGA
2G10.602 CAGCCTGCAGTCTGAAGATTT
CTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCG
VK3 (1-236) TGCAGTTTATTACTGTCAGCA
CCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAG p
VL]::huKLC GTATAACAACTGGCCTCTCAC
TCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCC
-CL + [hu TTTCGGCGGAGGGACCAAGGT
TCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAA
anti- GGAGATCAAACGAACGGTGG
TCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAG
<huGIPR> NA CTGCACCATCTGTCTTCATCTT
CCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCC
2G10.302 CCCGCCATCTGATGAGCAGTT
AGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCC
VH3 (1-472) GAAATCTGGAACTGCCTCTGT
CCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTG
VH]::huIgG1 TGTGTGCCTGCTGAATAACTT
AGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCT
zSEFL2-2 CTATCCCAGAGAGGCCAAAG
GAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCA
(mAb); LMR TACAGTGGAAGGTGGATAAC
TAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCAGC
ID: SS- GCCCTCCAATCGGGTAACTCC
ACGTACCGTTGCGTCAGCGTCCTCACCGTCCTGCACCAGGA
26227 CAGGAGAGTGTCACAGAGCA
CTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCCAACA
GGACAGCAAGGACAGCACCT AAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCC
ACAGCCTCAGCAGCACCCTGA AAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCC
CGCTGAGCAAAGCAGACTAC ATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCT
GAGAAACACAAAGTCTACGC GCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAG
1-3
CTGCGAAGTCACCCATCAGGG TGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCA
CCTGAGCTCGCCCGTCACAAA CGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATA
`z. GAGCTTCAACAGGGGAGAGT
GCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAA
oe
GT
CGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCA
CTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA
oe
cr
oe
146
A-2164-WO-PCT
(SEQ ID NO: 144) (SEQ ID NO: 145)
EIVMTQSPATLSVSPGERATLS QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMHWVRQAP
CRASQSVFEHLAWYQQKPGQA GEGLEWVAAIWFDASDKYYADAVKGRFTISRDNSKNTLYLQ
PRLLIYEAATRATGIPARVSGSG MNSLRAEDTAVYYCARDIAIFGVFPDYWGQGTLVTVSSASTK
SGTEFTLTISSLQSEDFAVYYCQ GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALT
oe
QYNNWPLTFGGGTKVEIKRTV SGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN
AAPSVFIFPPSDEQLKSGTASVV TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
AA
CLLNNFYPREAKVQWKVDNAL MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCE
QSGNSQESVTEQDSKDSTYSLS EQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI
STLTLSKADYEKHKVYACEVT SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV
HQGLSSPVTKSFNRGEC
EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN
VFSCSVMHEALHNHYTQKSLSLSPGK
(SEQ ID NO: 146) (SEQ ID NO: 147)
GAAATAGTGATGACGCAGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCC
CCAGCCACCCTGTCTGTGTCT TGGGAGGTCCCTGAGACTCTCCTGTGCAGCATCTGGATTCA
CCAGGGGAAAGAGCCACCCT CCTTCAGTAACTATGGCATGCACTGGGTCCGCCAGGCTCCA
p
CTCCTGCAGGGCCAGTCAGAG GGCGAGGGGCTGGAGTGGGTGGCAGCTATATGGTTTGATGC
[hu anti- TGTTTTCGAACACTTAGCCTG
AAGTGATAAATACTATGCAGACGCCGTGAAGGGCCGATTCA
<huGIPR> GTACCAGCAGAAACCTGGCC
CCATCTCCAGAGACAACTCCAAGAACACGCTGTATCTGCAA
2G10.325 AGGCTCCCAGGCTCCTCATCT
ATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTG
VK3 (1-236) ACGAAGCAGCCACCAGGGCC
TGCGAGAGATATTGCGATTTTTGGAGTGGTCCCCGACTACT
VL]::huKLC ACTGGTATCCCAGCCAGGTTC
GGGGCCAGGGAACCCTGGTCACCGTGTCTAGTGCCTCCACC
-CL + [hu AGTGGCAGTGGGTCTGGGAC
AAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAG
anti- AGAGTTCACTCTCACCATCAG
CACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGG
<huGIPR> NA CAGCCTGCAGTCTGAAGATTT ACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGC
2G10.325 TGCAGTTTATTACTGTCAGCA
GCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACA
VH3 (1-472) GTATAACCAGTGGCCTCTCAC
GTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGC
VH]::huIgG1 TTTCGGCGGAGGGACCAAGGT
CCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTG
z5EFL2-2 GGAGATCAAACGAACGGTGG
AATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTG
(mAb); LMR CTGCACCATCTGTCTTCATCTT
AGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGC
ID: SS- CCCGCCATCTGATGAGCAGTT
CCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTC
1-3
26202 GAAATCTGGAACTGCCTCTGT
CCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCC
TGTGTGCCTGCTGAATAACTT TGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACC
CTATCCCAGAGAGGCCAAAG CTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTG
oe
TACAGTGGAAGGTGGATAAC CATAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCA
GCCCTCCAATCGGGTAACTCC GCACGTACCGTTGCGTCAGCGTCCTCACCGTCCTGCACCAG
oe
oe
147
A-2164-WO-PCT
CAGGAGAGTGTCACAGAGCA GACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCCA
GGACAGCAAGGACAGCACCT ACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAA
ACAGCCTCAGCAGCACCCTGA GCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCC
CGCTGAGCAAAGCAGACTAC CCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTG
GAGAAACACAAAGTCTACGC ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGT
CTGCGAAGTCACCCATCAGGG GGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAG
CCTGAGCTCGCCCGTCACAAA ACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTC
GAGCTTCAACAGGGGAGAGT TATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGG
GT
GGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCAC
AACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAA
A
(SEQ ID NO: 148) (SEQ ID NO: 149)
EIVMTQ SP ATL SVSPGERATLS QVQLVE SGGGVVQPGRSLRL SCAA S GFTF SNYGMHWVRQ AP
CRASQSVFEHLAWYQQKPGQA GEGLEWVAAIWFDASDKYYADAVKGRFTISRDNSKNTLYLQ
PRLLIYEAATRATGIPARFSGSG MNSLRAEDTAVYYCARDIAIFGVVPDYWGQGTLVTVSSASTK
SGTEFTLTIS SLQSEDFAVYYCQ GP SVFPL AP S SKST S GGT AALGCL VKDYFPEPVTVSWN S GAL
T
QYNQWPLTFGGGTKVEIKRTV SGVHTFPAVLQS SGLY SLS SVVTVP S S SLGTQTYICNVNHKP SN
AA AAP SVFIFPP SDEQLKSGTASVV
TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
CLLNNFYPREAKVQWKVDNAL MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCE
QSGNSQESVTEQD SKD STY SL S EQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI
STLTLSKADYEKHKVYACEVT SKAKGQPREPQVYTLPP SREEMTKNQVSLTCLVKGFYP SDIAV
HQGL S SPVTKSFNRGEC EWE SNGQPENNYKTTPPVLD SD
GSFFLY SKL TVD KSRWQQ GN
VFSCSVMHEALHNHYTQKSLSLSPGK
(SEQ ID NO: 150) (SEQ ID NO: 151)
[hu anti- GAAATAGTGATGACGCAGTCT
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCC
<huGIPR> CCAGCCACCCTGTCTGTGTCT
TGGGAGGTCCCTGAGACTCTCCTGTGCAGCATCTGGATTCA
2G10.343 CCAGGGGAAAGAGCCACCCT
CCTTCAGTAACTATGGCATGCACTGGGTCCGCCAGGCTCCA
VK3 (1-236) CTCCTGCAGGGCCAGTCAGAG
GGCGAGGGGCTGGAGTGGGTGGCAGCTATATGGTTTGATGC
VL]::huKLC TGTTCTGGAACACTTAGCCTG
AAGTGATAAATACTATGCAGACGCCGTGAAGGGCCGATTCA
-CL + [hu A N GTACCAGCAGAAACCTGGCC
CCATCTCCAGAGACAACTCCAAGAACACGCTGTATCTGCAA
anti- AGGCTCCCAGGCTCCTCATCT
ATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTG 1-3
<huGIPR> ACGAAGCAGCCACCAGGGCC
TGCGAGAGATATTGCGATTTTTGGAGTGGTCCCCGACTACT
2G10.325 ACTGGTATCCCAGCCAGGTTC
GGGGCCAGGGAACCCTGGTCACCGTGTCTAGTGCCTCCACC
re)
c5 VH3 (1-472) AGTGGCAGTGGGTCTGGGAC
AAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAG
VH]::huIgG1 AGAGTTCACTCTCACCATCAG
CACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGG
zSEFL2-2 CAGCCTGCAGTCTGAAGATTT
ACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGC oe
oe
148
A-2164-WO-PCT
(mAb); LMR TGCAGTTTATTACTGTCAGCA
GCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACA
ID: SS- GTATAACAACTGGCCTCTCAC
GTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGC
26220 TTTCGGCGGAGGGACCAAGGT
CCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTG
GGAGATCAAACGAACGGTGG AATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTG
CTGCACCATCTGTCTTCATCTT AGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGC
CCCGCCATCTGATGAGCAGTT CCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTC
GAAATCTGGAACTGCCTCTGT CCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCC
TGTGTGCCTGCTGAATAACTT TGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACC
CTATCCCAGAGAGGCCAAAG CTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTG
TACAGTGGAAGGTGGATAAC CATAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCA
GCCCTCCAATCGGGTAACTCC GCACGTACCGTTGCGTCAGCGTCCTCACCGTCCTGCACCAG
CAGGAGAGTGTCACAGAGCA GACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCCA
GGACAGCAAGGACAGCACCT ACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAA
ACAGCCTCAGCAGCACCCTGA GCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCC
CGCTGAGCAAAGCAGACTAC CCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTG
GAGAAACACAAAGTCTACGC ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGT
CTGCGAAGTCACCCATCAGGG GGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAG
CCTGAGCTCGCCCGTCACAAA ACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTC
GAGCTTCAACAGGGGAGAGT TATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGG
GT
GGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCAC
AACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAA
A
(SEQ ID NO: 152) (SEQ ID NO: 153)
EIVMTQSPATLSVSPGERATLS QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMHWVRQAP
CRASQSVLEHLAWYQQKPGQA GEGLEWVAAIWFDASDKYYADAVKGRFTISRDNSKNTLYLQ
PRLLIYEAATRATGIPARFSGSG MNSLRAEDTAVYYCARDIAIFGVVPDYWGQGTLVTVSSASTK
SGTEFTLTISSLQSEDFAVYYCQ GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALT
QYNNWPLTFGGGTKVEIKRTV SGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN
AA AAPSVFIFPPSDEQLKSGTASVV TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
CLLNNFYPREAKVQWKVDNAL MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCE
QSGNSQESVTEQDSKDSTYSLS EQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI
1-3
STLTLSKADYEKHKVYACEVT SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV
HQGLSSPVTKSFNRGEC
EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN
VFSCSVMHEALHNHYTQKSLSLSPGK
oe
(SEQ ID NO: 154) (SEQ ID NO: 155)
" [hu anti- NA GAAATAGTGATGACGCAGTCT
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCC oe
oe
149
A-2164-WO-PCT
<huGIPR> CCAGCCACCCTGTCTGTGTCT
TGGGAGGTCCCTGAGACTCTCCTGTGCAGCATCTGGATTCA
2G10.307 CCAGGGGAAAGAGCCACCCT
CCTTCAGTAACTATGGCATGCACTGGGTCCGCCAGGCTCCA
VK3 (1-236) CTCCTGCAGGGCCAGTCAGAG
GGCGAGGGGCTGGAGTGGGTGGCAGCTATATGGTTTGATGC
VL]::huKLC TGTTGATAGACACTTAGCCTG
AAGTGATAAATACTATGCAGACGCCGTGAAGGGCCGATTCA
-CL + [hu GTACCAGCAGAAACCTGGCC
CCATCTCCAGAGACAACTCCAAGAACACGCTGTATCTGCAA
anti- AGGCTCCCAGGCTCCTCATCT
ATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTG
<huGIPR> ACGAAGCAGCCACCAGGGCC
TGCGAGAGATATTGCGATTTTTGGAGTGTTTCCCGACTACTG
2G10.302 ACTGGTATCCCAGCCAGGTTC
GGGCCAGGGAACCCTGGTCACCGTGTCTAGTGCCTCCACCA
VH3 (1-472) AGTGGCAGTGGGTCTGGGAC
AGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGC
VH]::huIgG1 AGAGTTCACTCTCACCATCAG
ACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGA
zSEFL2-2 CAGCCTGCAGTCTGAAGATTT
CTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCG
(mAb); LMR TGCAGTTTATTACTGTCAGCA
CCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAG
ID: SS- GTATAACCAGTGGCCTCTCAC
TCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCC
26190 TTTCGGCGGAGGGACCAAGGT
TCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAA
GGAGATCAAACGAACGGTGG TCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAG
CTGCACCATCTGTCTTCATCTT CCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCC
CCCGCCATCTGATGAGCAGTT AGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCC
GAAATCTGGAACTGCCTCTGT CCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTG
TGTGTGCCTGCTGAATAACTT AGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCT
CTATCCCAGAGAGGCCAAAG GAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCA
TACAGTGGAAGGTGGATAAC TAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCAGC
GCCCTCCAATCGGGTAACTCC ACGTACCGTTGCGTCAGCGTCCTCACCGTCCTGCACCAGGA
CAGGAGAGTGTCACAGAGCA CTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCCAACA
GGACAGCAAGGACAGCACCT AAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCC
ACAGCCTCAGCAGCACCCTGA AAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCC
CGCTGAGCAAAGCAGACTAC ATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCT
GAGAAACACAAAGTCTACGC GCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAG
CTGCGAAGTCACCCATCAGGG TGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCA
CCTGAGCTCGCCCGTCACAAA CGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATA
GAGCTTCAACAGGGGAGAGT GCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAA
GT
CGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCA
1-3
CTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA
(SEQ ID NO: 156) (SEQ ID NO: 157)
EIVMTQSPATLSVSPGERATLS QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMHWVRQAP
oe
AA CRASQSVDRHLAWYQQKPGQ GEGLEWVAAIWFDASDKYYADAVKGRFTISRDNSKNTLYLQ
APRLLIYEAATRATGIPARFSGS MNSLRAEDTAVYYCARDIAIFGVFPDYWGQGTLVTVSSASTK
oe
oe
150
A-2164-WO-PCT
GSGTEFTLTISSLQSEDFAVYYC GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALT
QQYNQWPLTFGGGTKVEIKRT SGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN
VAAPSVFIFPPSDEQLKSGTASV TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
VCLLNNFYPREAKVQWKVDN MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCE
ALQSGNSQESVTEQDSKDSTYS EQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI
LSSTLTLSKADYEKHKVYACE SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV
VTHQGLSSPVTKSFNRGEC
EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN
VFSCSVMHEALHNHYTQKSLSLSPGK
(SEQ ID NO: 158) (SEQ ID NO: 159)
GAAATAGTGATGACGCAGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCC
CCAGCCACCCTGTCTGTGTCT TGGGAGGTCCCTGAGACTCTCCTGTGCAGCATCTGGATTCA
CCAGGGGAAAGAGCCACCCT CCTTCAGTAACTATGGCATGCACTGGGTCCGCCAGGCTCCA
CTCCTGCAGGGCCAGTCAGAG GGCGAGGGGCTGGAGTGGGTGGCAGCTATATGGTTTGATGC
TGTTAACCGGCACTTAGCCTG AAGTGATAAATACTATGCAGACGCCGTGAAGGGCCGATTCA
GTACCAGCAGAAACCTGGCC CCATCTCCAGAGACAACTCCAAGAACACGCTGTATCTGCAA
[hu anti- AGGCTCCCAGGCTCCTCATCT
ATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTG
<huGIPR> ACGAAGCAGCCACCAGGGCC
TGCGAGAGATATTGCGATTTTTGGAGTGTTTCCCGACTACTG
2G10.317 ACTGGTATCCCAGCCAGGTTC
GGGCCAGGGAACCCTGGTCACCGTGTCTAGTGCCTCCACCA
VK3 (1-236) AGTGGCAGTGGGTCTGGGAC
AGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGC
VL]::huKLC AGAGTTCACTCTCACCATCAG
ACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGA
-CL + [hu CAGCCTGCAGTCTGAAGATTT
CTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCG
anti- TGCAGTTTATTACTGTCAGCA
CCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAG
<huGIPR> NA GTATCAGCAGTGGCCTCTCAC TCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCC
2G10.302 TTTCGGCGGAGGGACCAAGGT
TCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAA
VH3 (1-472) GGAGATCAAACGAACGGTGG
TCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAG
VH]::huIgG1 CTGCACCATCTGTCTTCATCTT
CCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCC
zSEFL2-2 CCCGCCATCTGATGAGCAGTT
AGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCC
(mAb); LMR GAAATCTGGAACTGCCTCTGT
CCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTG
ID: SS- TGTGTGCCTGCTGAATAACTT
AGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCT
26194 CTATCCCAGAGAGGCCAAAG
GAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCA
TACAGTGGAAGGTGGATAAC TAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCAGC
1-3
GCCCTCCAATCGGGTAACTCC ACGTACCGTTGCGTCAGCGTCCTCACCGTCCTGCACCAGGA
CAGGAGAGTGTCACAGAGCA CTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCCAACA
GGACAGCAAGGACAGCACCT AAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCC
oe
ACAGCCTCAGCAGCACCCTGA AAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCC
CGCTGAGCAAAGCAGACTAC ATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCT
oe
oe
151
A-2164-WO-PCT
GAGAAACACAAAGTCTACGC GCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAG
CTGCGAAGTCACCCATCAGGG TGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCA
CCTGAGCTCGCCCGTCACAAA CGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATA
GAGCTTCAACAGGGGAGAGT GCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAA
GT
CGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCA
CTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA
(SEQ ID NO: 160) (SEQ ID NO: 161)
EIVMTQ SP ATL SVSPGERATLS QVQLVE SGGGVVQPGRSLRL SCAA S GFTF SNYGMHWVRQ AP
CRASQSVNRHLAWYQQKPGQ GEGLEWVAAIWFDASDKYYADAVKGRFTISRDNSKNTLYLQ
APRLLIYEAATRATGIPARFSGS MNSLRAEDTAVYYCARDIAIFGVFPDYWGQGTLVTVSSASTK
GS GTEFTL TI S SLQSEDFAVYYC GP SVFPL AP S SKST S GGT AALGCL VKDYFPEPVTVSWN S
GAL T
QQYQQWPLTFGGGTKVEIKRT SGVHTFPAVLQS SGLY SLS SVVTVP S S SLGTQTYICNVNHKP SN
AA VAAPSVFIFPPSDEQLKSGTASV TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
VCLLNNFYPREAKVQWKVDN MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCE
ALQSGNSQESVTEQDSKDSTYS EQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI
L SSTLTL SKADYEKHKVYACE SKAKGQPREPQVYTLPP SREEMTKNQVSLTCLVKGFYP SDIAV
VTHQGLSSPVTKSFNRGEC
EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN
VFSCSVMHEALHNHYTQKSLSLSPGK
(SEQ ID NO: 162) (SEQ ID NO: 163)
GAAATAGTGATGACGCAGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCC
[hu anti- CCAGCCACCCTGTCTGTGTCT
TGGGAGGTCCCTGAGACTCTCCTGTGCAGCATCTGGATTCA
<huGIPR> CCAGGGGAAAGAGCCACCCT
CCTTCAGTAACTATGGCATGCACTGGGTCCGCCAGGCTCCA
2G10.311 CTCCTGCAGGGCCAGTCAGAG
GGCGAGGGGCTGGAGTGGGTGGCAGCTATATGGTTTGATGC
VK3 (1-236) TGTTAACGTACACTTAGCCTG
AAGTGATAAATACTATGCAGACGCCGTGAAGGGCCGATTCA
VL]::huKLC GTACCAGCAGAAACCTGGCC
CCATCTCCAGAGACAACTCCAAGAACACGCTGTATCTGCAA
-CL + [hu AGGCTCCCAGGCTCCTCATCT
ATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTG
anti- ACCAGGCAGCCACCAGGGCC
TGCGAGAGATATTGCGATTTTTGGAGTGTTTCCCGACTACTG
<huGIPR> NA ACTGGTATCCCAGCCAGGTTC GGGCCAGGGAACCCTGGTCACCGTGTCTAGTGCCTCCACCA
2G10.302 AGTGGCAGTGGGTCTGGGAC
AGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGC
VH3 (1-472) AGAGTTCACTCTCACCATCAG
ACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGA
VH]::huIgG1 CAGCCTGCAGTCTGAAGATTT
CTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCG 1-3
zSEFL2-2 TGCAGTTTATTACTGTCAGCA
CCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAG
(mAb); LMR GTATAACCAGTGGCCTCTCAC
TCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCC
re)
c5 ID: SS- TTTCGGCGGAGGGACCAAGGT
TCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAA
26188 GGAGATCAAACGAACGGTGG
TCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAG
CTGCACCATCTGTCTTCATCTT CCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCC
oe
oe
152
A-2164-WO-PCT
CCCGCCATCTGATGAGCAGTT AGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCC
GAAATCTGGAACTGCCTCTGT CCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTG
TGTGTGCCTGCTGAATAACTT AGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCT
CTATCCCAGAGAGGCCAAAG GAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCA
TACAGTGGAAGGTGGATAAC TAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCAGC
GCCCTCCAATCGGGTAACTCC ACGTACCGTTGCGTCAGCGTCCTCACCGTCCTGCACCAGGA
CAGGAGAGTGTCACAGAGCA CTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCCAACA
GGACAGCAAGGACAGCACCT AAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCC
ACAGCCTCAGCAGCACCCTGA AAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCC
CGCTGAGCAAAGCAGACTAC ATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCT
GAGAAACACAAAGTCTACGC GCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAG
CTGCGAAGTCACCCATCAGGG TGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCA
CCTGAGCTCGCCCGTCACAAA CGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATA
GAGCTTCAACAGGGGAGAGT GCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAA
GT
CGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCA
CTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA
(SEQ ID NO: 164) (SEQ ID NO: 165)
EIVMTQ SP ATL SVSPGERATLS QVQLVE SGGGVVQPGRSLRL SCAASGFTFSNYGMHWVRQAP
CRASQSVNVHLAWYQQKPGQ GEGLEWVAAIWFDASDKYYADAVKGRFTISRDNSKNTLYLQ
APRLLIYQAATRATGIPARFSGS MNSLRAEDTAVYYCARDIAIFGVFPDYWGQGTLVTVSSASTK
GS GTEFTL TI S SLQSEDFAVYYC GP SVFPL AP S SKST S GGTAALGCLVKDYFPEPVTVSWN S GAL
T
QQYNQWPLTFGGGTKVEIKRT SGVHTFPAVLQS SGLY SLS SVVTVP S S SLGTQTYICNVNHKP SN
VAAPSVFIFPPSDEQLKSGTASV TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
AA
VCLLNNFYPREAKVQWKVDN MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCE
ALQSGNSQESVTEQD SKD STY S EQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI
L SSTLTL SKADYEKHKVYACE SKAKGQPREPQVYTLPP SREEMTKNQVSLTCLVKGFYP SDIAV
VTHQGLSSPVTKSFNRGEC EWE SNGQPENNYKTTPPVLD SD
GSFFLY SKL TVD KSRWQQ GN
VFSCSVMHEALHNHYTQKSLSLSPGK
(SEQ ID NO: 166) (SEQ ID NO: 167)
[hu anti- GAAATAGTGATGACGCAGTCT
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCC
<huGIPR> CCAGCCACCCTGTCTGTGTCT
TGGGAGGTCCCTGAGACTCTCCTGTGCAGCATCTGGATTCA 1-3
2G10.306 CCAGGGGAAAGAGCCACCCT
CCTTCAGTAACTATGGCATGCACTGGGTCCGCCAGGCTCCA
VK3 (1-236) NA CTCCTGCAGGGCCAGTCAGAG GGCGAGGGGCTGGAGTGGGTGGCAGCTATATGGTTTGATGC
re)
VL]::huKLC TGTTCTGACGCACTTAGCCTG
AAGTGATAAATACTATGCAGACGCCGTGAAGGGCCGATTCA
-CL + [hu GTACCAGCAGAAACCTGGCC
CCATCTCCAGAGACAACTCCAAGAACACGCTGTATCTGCAA
" anti- AGGCTCCCAGGCTCCTCATCT
ATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTG oe
oe
153
A-2164-WO-PCT
<huGIPR> ACGAAGCAGCCACCAGGGCC
TGCGAGAGATATTGCGATTTTTGGAGTGATCCCCGACTACT
2G10.306 ACTGGTATCCCAGCCAGGTTC
GGGGCCAGGGAACCCTGGTCACCGTGTCTAGTGCCTCCACC
VH3 (1-472) AGTGGCAGTGGGTCTGGGAC
AAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAG
VH]::huIgG1 AGAGTTCACTCTCACCATCAG
CACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGG
zSEFL2-2 CAGCCTGCAGTCTGAAGATTT
ACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGC
(mAb); LMR TGCAGTTTATTACTGTCAGCA
GCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACA
ID: SS- GTATCAGAACTGGCCTCTCAC
GTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGC
26183 TTTCGGCGGAGGGACCAAGGT
CCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTG
GGAGATCAAACGAACGGTGG AATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTG
CTGCACCATCTGTCTTCATCTT AGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGC
CCCGCCATCTGATGAGCAGTT CCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTC
GAAATCTGGAACTGCCTCTGT CCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCC
TGTGTGCCTGCTGAATAACTT TGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACC
CTATCCCAGAGAGGCCAAAG CTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTG
TACAGTGGAAGGTGGATAAC CATAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCA
GCCCTCCAATCGGGTAACTCC GCACGTACCGTTGCGTCAGCGTCCTCACCGTCCTGCACCAG
CAGGAGAGTGTCACAGAGCA GACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCCA
GGACAGCAAGGACAGCACCT ACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAA
ACAGCCTCAGCAGCACCCTGA GCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCC
CGCTGAGCAAAGCAGACTAC CCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTG
GAGAAACACAAAGTCTACGC ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGT
CTGCGAAGTCACCCATCAGGG GGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAG
CCTGAGCTCGCCCGTCACAAA ACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTC
GAGCTTCAACAGGGGAGAGT TATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGG
GT
GGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCAC
AACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAA
A
(SEQ ID NO: 168) (SEQ ID NO: 169)
EIVMTQSPATLSVSPGERATLS QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMHWVRQAP
CRASQSVLTHLAWYQQKPGQA GEGLEWVAAIWFDASDKYYADAVKGRFTISRDNSKNTLYLQ
PRLLIYEAATRATGIPARFSGSG MNSLRAEDTAVYYCARDIAIFGVIPDYWGQGTLVTVSSASTKG
AA SGTEFTLTISSLQSEDFAVYYCQ PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS
QYQNWPLTFGGGTKVEIKRTV GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNT
AAPSVFIFPPSDEQLKSGTASVV KVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMI
oe
CLLNNFYPREAKVQWKVDNAL SRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCEEQ
QSGNSQESVTEQDSKDSTYSLS YGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISK
oe
oe
154
A-2164-WO-PCT
STLTLSKADYEKHKVYACEVT AKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEW
HQGLSSPVTKSFNRGEC
ESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS
CSVMHEALHNHYTQKSLSLSPGK
(SEQ ID NO: 170) (SEQ ID NO: 171)
GAAATAGTGATGACGCAGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCC
oe
CCAGCCACCCTGTCTGTGTCT TGGGAGGTCCCTGAGACTCTCCTGTGCAGCATCTGGATTCA
CCAGGGGAAAGAGCCACCCT CCTTCAGTAACTATGGCATGCACTGGGTCCGCCAGGCTCCA
CTCCTGCAGGGCCAGTCAGAG GGCGAGGGGCTGGAGTGGGTGGCAGCTATATGGTTTGATGC
TGTTCTGACGCACTTAGCCTG AAGTGATAAATACTATGCAGACGCCGTGAAGGGCCGATTCA
GTACCAGCAGAAACCTGGCC CCATCTCCAGAGACAACTCCAAGAACACGCTGTATCTGCAA
AGGCTCCCAGGCTCCTCATCT ATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTG
ACGAAGCAGCCACCAGGGCC TGCGAGAGATATTGCGATTTTTGGAGTGATCCCCGACTACT
ACTGGTATCCCAGCCAGGGTC GGGGCCAGGGAACCCTGGTCACCGTGTCTAGTGCCTCCACC
[hu anti-
AGTGGCAGTGGGTCTGGGAC AAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAG
<huGIPR>
AGAGTTCACTCTCACCATCAG CACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGG
2G10.606
VK3 1 236)
CAGCCTGCAGTCTGAAGATTT ACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGC
- (
TGCAGTTTATTACTGTCAGCA GCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACA
VL]::huKLC
GTATCAGAACTGGCCTCTCAC GTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGC
-CL + [hu
TTTCGGCGGAGGGACCAAGGT CCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTG
anti-
GGAGATCAAACGAACGGTGG AATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTG
<huGIPR> NA
CTGCACCATCTGTCTTCATCTT AGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGC
2G10.306
CCCGCCATCTGATGAGCAGTT CCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTC
VH3 (1-472)
GAAATCTGGAACTGCCTCTGT CCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCC
VH]::huIgG1
TGTGTGCCTGCTGAATAACTT TGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACC
zSEFL2-2
Ab); LMR CTATCCCAGAGAGGCCAAAG
CTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTG
(m
SS-
TACAGTGGAAGGTGGATAAC CATAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCA
26231
ID:
GCCCTCCAATCGGGTAACTCC GCACGTACCGTTGCGTCAGCGTCCTCACCGTCCTGCACCAG
CAGGAGAGTGTCACAGAGCA GACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCCA
GGACAGCAAGGACAGCACCT ACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAA
ACAGCCTCAGCAGCACCCTGA GCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCC
CGCTGAGCAAAGCAGACTAC CCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTG
1-3
GAGAAACACAAAGTCTACGC ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGT
CTGCGAAGTCACCCATCAGGG GGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAG
`z. CCTGAGCTCGCCCGTCACAAA
ACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTC
oe
GAGCTTCAACAGGGGAGAGT TATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGG
GT
GGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCAC
oe
cr
oe
155
A-2164-WO-PCT
AACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAA
A
(SEQ ID NO: 172) (SEQ ID NO: 173)
0
EIVMTQ SP ATL SVSPGERATLS QVQLVE SGGGVVQPGRSLRL SCAA S GFTF SNYGMHWVRQ AP
CRASQSVLTHLAWYQQKPGQA GEGLEWVAAIWFDASDKYYADAVKGRFTISRDNSKNTLYLQ
oe
PRLLIYEAATRATGIPARVSGSG MNSLRAEDTAVYYCARDIAIFGVIPDYWGQGTLVTVSSASTKG
SGTEFTLTIS SLQSEDFAVYYCQ P SVFPLAP S SKST S GGT AALGCL VKDYFPEPVTVSWN S GALT S
QYQNWPLTFGGGTKVEIKRTV GVHTFPAVLQSSGLYSLSSVVTVP SSSLGTQTYICNVNHKPSNT
AAPSVFIFPPSDEQLKSGTASVV KVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMI
AA
CLLNNFYPREAKVQWKVDNAL SRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCEEQ
QSGNSQESVTEQD SKD STY SL S YGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISK
STLTLSKADYEKHKVYACEVT AKGQPREPQVYTLPP SREEMTKNQVSLTCLVKGFYP SDIAVEW
HQGL S SPVTKSFNRGEC E SNGQPENNYKTTPPVLD SD GSFFLY
SKLTVDKSRWQQGNVFS
C SVMHEALHNHYTQKSL SL SP GK
(SEQ ID NO: 174) (SEQ ID NO: 175)
GAAATAGTGATGACGCAGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCC
p
CCAGCCACCCTGTCTGTGTCT TGGGAGGTCCCTGAGACTCTCCTGTGCAGCATCTGGATTCA
anti- CCAGGGGAAAGAGCCACCCT
CCTTCAGTAACTATGGCATGCACTGGGTCCGCCAGGCTCCA
<huGIPR> CTCCTGCAGGGCCAGTCAGAG
GGCGAGGGGCTGGAGTGGGTGGCAGCTATATGGTTTGATGC
21- TGTTAGCAGCAACTTAGCCTG
AAGTGATAAATACTATGCAGACGCCGTGAAGGGCCGATTCA
143 2G10_L GTACCAGCAGAAACCTGGCC
CCATCTCCAGAGACAACTCCAAGAACACGCTGTATCTGCAA
C1.005 (1- AGGCTCCCAGGCTCCTCATCT
ATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTG
237) (S 73 (85) ATGGTGCAGCCACCAGGGCC
TGCGAGAGATTTGGCGATTTTTGGAGTGGTCCCCGACTACT
A) VL + ACTGGTATCCCAGCCAGGTTC
GGGGCCAGGGAACCCTGGTCACCGTGTCTAGTGCCTCCACC
[Unknown AGTGGCAGTGGGTCTGGGAC
AAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAG
anti- NA AGAGTTCACTCTCACCATCAG
CACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGG
<huGIPR> CAGCCTGCAGTCTGAAGATTT
ACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGC
2G10.610 TGCAGTTTATTACTGTCAGCA
GCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACA
VH3 (1-472) GTATAATAACTGGCCTCTCAC
GTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGC
VH]::huIgG1 TTTCGGCGGAGGGACCAAGGT
CCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTG
z5EFL2-2 GGAGATCAAACGAACGGTGG
AATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTG 1-3
(mAb); LMR CTGCACCATCTGTCTTCATCTT
AGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGC
ID: SS- CCCGCCATCTGATGAGCAGTT
CCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTC
re)
c:5 26224 GAAATCTGGAACTGCCTCTGT
CCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCC
oe
TGTGTGCCTGCTGAATAACTT TGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACC
CTATCCCAGAGAGGCCAAAG CTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTG
oe
cr
oe
156
A-2164-W0- P CT
TACAGTGGAAGGTGGATAAC CATAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCA
GCCCTCCAATCGGGTAACTCC GCACGTACCGTTGCGTCAGCGTCCTCACCGTCCTGCACCAG
CAGGAGAGTGTCACAGAGCA GACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCCA
0
GGACAGCAAGGACAGCACCT ACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAA
n.)
o
ACAGCCTCAGCAGCACCCTGA GCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCC
oe
i-J
CGCTGAGCAAAGCAGACTAC CCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTG
c,.)
--.1
GAGAAACACAAAGTCTACGC ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGT
o
vo
CTGCGAAGTCACCCATCAGGG GGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAG
--.1
CCTGAGCTCGCCCGTCACAAA ACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTC
GAGCTTCAACAGGGGAGAGT TATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGG
GT
GGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCAC
AACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAA
A
(SEQ ID NO: 176) (SEQ ID NO: 177)
EIVMTQ SP ATL SVSPGERATLS QVQLVE SGGGVVQPGRSLRL SCAASGFTFSNYGMHWVRQAP
CRASQ S VS SNLAWYQQKPGQA GEGLEWVAAIWFDASDKYYADAVKGRFTISRDNSKNTLYLQ
P
PRLLIYGAATRATGIPARFSGSG MNSLRAEDTAVYYCARDLAIFGVVPDYWGQGTLVTVSSASTK
SGTEFTLTIS SLQSEDFAVYYCQ GP SVFPL AP S SKST S GGT AALGCL VKDYFPEPVTVSWN S GAL
T .
,
QYNNWPLTFGGGTKVEIKRTV SGVHTFPAVLQS SGLY SLS SVVTVP S S SLGTQTYICNVNHKP SN
' AA AAP SVFIFPP SDEQLKSGTASVV
TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL " CLLNNFYPREAKVQWKVDNAL
MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCE y
,
QSGNSQESVTEQD SKD STY SL S EQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI
.
,
STLTLSKADYEKHKVYACEVT SKAKGQPREPQVYTLPP SREEMTKNQVSLTCLVKGFYP SDIAV
,
HQGL S SPVTKSFNRGEC EWE SNGQPENNYKTTPPVLD SD
GSFFLY SKL TVD KSRWQQ GN
VFSCSVMHEALHNHYTQKSLSLSPGK
(SEQ ID NO: 178) (SEQ ID NO: 179)
anti- GAAATAGTGATGACGCAGTCT
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCC
<huGIPR> CCAGCCACCCTGTCTGTGTCT
TGGGAGGTCCCTGAGACTCTCCTGTGCAGCATCTGGATTCA
21- CCAGGGGAAAGAGCCACCCT
CCTTCAGTAACTATGGCATGCACTGGGTCCGCCAGGCTCCA
143 2G1O_L CTCCTGCAGGGCCAGTCAGAG
GGCGAGGGGCTGGAGTGGGTGGCAGCTATATGGTTTGATGC 00
n
C1.005 (1- NA TGTTAGCAGCAACTTAGCCTG
AAGTGATAAATACTATGCAGACGCCGTGAAGGGCCGATTCA 1-3
237) (S 73 (85) GTACCAGCAGAAACCTGGCC
CCATCTCCAGAGACAACTCCAAGAACACGCTGTATCTGCAA
cp
4 A) VL + [hu AGGCTCCCAGGCTCCTCATCT
ATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTG n.)
o
g anti- ATGGTGCAGCCACCAGGGCC
TGCGAGAGATCAGGCGATTTTTGGAGTGGTCCCCGATTACT
<huGIPR> ACTGGTATCCCAGCCAGGTTC
GGGGCCAGGGAACCCTGGTCACCGTGTCTAGTGCCTCCACC 'a
2G10.348 AGTGGCAGTGGGTCTGGGAC
AAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAG oe
c:
oe
157
A-2164-WO-PCT
VH3 (1-472) AGAGTTCACTCTCACCATCAG
CACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGG
VH]::huIgG1 CAGCCTGCAGTCTGAAGATTT
ACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGC
zSEFL2-2 TGCAGTTTATTACTGTCAGCA
GCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACA
(mAb); LMR GTATAATAACTGGCCTCTCAC
GTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGC
ID: SS- TTTCGGCGGAGGGACCAAGGT
CCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTG
26225 GGAGATCAAACGAACGGTGG
AATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTG
CTGCACCATCTGTCTTCATCTT AGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGC
CCCGCCATCTGATGAGCAGTT CCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTC
GAAATCTGGAACTGCCTCTGT CCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCC
TGTGTGCCTGCTGAATAACTT TGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACC
CTATCCCAGAGAGGCCAAAG CTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTG
TACAGTGGAAGGTGGATAAC CATAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCA
GCCCTCCAATCGGGTAACTCC GCACGTACCGTTGCGTCAGCGTCCTCACCGTCCTGCACCAG
CAGGAGAGTGTCACAGAGCA GACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCCA
GGACAGCAAGGACAGCACCT ACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAA
ACAGCCTCAGCAGCACCCTGA GCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCC
CGCTGAGCAAAGCAGACTAC CCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTG
GAGAAACACAAAGTCTACGC ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGT
CTGCGAAGTCACCCATCAGGG GGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAG
CCTGAGCTCGCCCGTCACAAA ACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTC
GAGCTTCAACAGGGGAGAGT TATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGG
GT
GGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCAC
AACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAA
A
(SEQ ID NO: 180) (SEQ ID NO: 181)
EIVMTQSPATLSVSPGERATLS QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMHWVRQAP
CRASQSVSSNLAWYQQKPGQA GEGLEWVAAIWFDASDKYYADAVKGRFTISRDNSKNTLYLQ
PRLLIYGAATRATGIPARFSGSG MNSLRAEDTAVYYCARDQAIFGVVPDYWGQGTLVTVSSASTK
SGTEFTLTISSLQSEDFAVYYCQ GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALT
QYNNWPLTFGGGTKVEIKRTV SGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN
AA AAPSVFIFPPSDEQLKSGTASVV TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
1-3
CLLNNFYPREAKVQWKVDNAL MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCE
QSGNSQESVTEQDSKDSTYSLS EQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI
STLTLSKADYEKHKVYACEVT SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV
oe
HQGLSSPVTKSFNRGEC
EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN
VFSCSVMHEALHNHYTQKSLSLSPGK
oe
oe
158
A-2164-WO-P CT
(SEQ ID NO: 182) (SEQ ID NO: 183)
GAAATAGTGATGACGCAGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCC
CCAGCCACCCTGTCTGTGTCT TGGGAGGTCCCTGAGACTCTCCTGTGCAGCATCTGGATTCA
CCAGGGGAAAGAGCCACCCT CCTTCAGTAACTATGGCATGCACTGGGTCCGCCAGGCTCCA
CTCCTGCAGGGCCAGTCAGAG GGCGAGGGGCTGGAGTGGGTGGCAGCTATATGGTTTGATGC
oe
TGTTAGCAGCAACTTAGCCTG AAGTGATAAATACTATGCAGACGCCGTGAAGGGCCGATTCA
GTACCAGCAGAAACCTGGCC CCATCTCCAGAGACAACTCCAAGAACACGCTGTATCTGCAA
AGGCTCCCAGGCTCCTCATCT ATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTG
ATGGTGCAGCCACCAGGGCC TGCGAGAGATATTGCGATTTTTGGAGTGGTCCCCGACTACT
ACTGGTATCCCAGCCAGGTTC GGGGCCAGGGAACCCTGGTCACCGTGTCTAGTGCCTCCACC
AGTGGCAGTGGGTCTGGGAC AAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAG
anti-
AGAGTTCACTCTCACCATCAG CACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGG
<huGIPR>
CAGCCTGCAGTCTGAAGATTT ACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGC
21-
TGCAGTTTATTACTGTCAGCA GCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACA
143 2G1O_L
GTATAATAACTGGCCTCTCAC GTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGC
C1.005 (1-
TTTCGGCGGAGGGACCAAGGT CCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTG
237) (S 73 (85)
GGAGATCAAACGAACGGTGG AATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTG
A) VL + [hu
CTGCACCATCTGTCTTCATCTT AGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGC
anti-
NA CCCGCCATCTGATGAGCAGTT CCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTC
<huGIPR>
GAAATCTGGAACTGCCTCTGT CCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCC
2G10.325
VH3(1-472)
TGTGTGCCTGCTGAATAACTT TGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACC
CTATCCCAGAGAGGCCAAAG CTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTG
VH]::huIgG1
TACAGTGGAAGGTGGATAAC CATAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCA
zSEFL2-2
GCCCTCCAATCGGGTAACTCC GCACGTACCGTTGCGTCAGCGTCCTCACCGTCCTGCACCAG
(m b), LMR
CAGGAGAGTGTCACAGAGCA GACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCCA
ID: SS-
GGACAGCAAGGACAGCACCT ACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAA
26223
ACAGCCTCAGCAGCACCCTGA GCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCC
CGCTGAGCAAAGCAGACTAC CCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTG
GAGAAACACAAAGTCTACGC ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGT
CTGCGAAGTCACCCATCAGGG GGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAG
CCTGAGCTCGCCCGTCACAAA ACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTC
1-3
GAGCTTCAACAGGGGAGAGT TATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGG
GT
GGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCAC
AACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAA
oe
A
(SEQ ID NO: 184) (SEQ ID NO: 185)
oe
cr
oe
159
A-2164-WO-PCT
EIVMTQSPATLSVSPGERATLS QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMHWVRQAP
CRASQSVSSNLAWYQQKPGQA GEGLEWVAAIWFDASDKYYADAVKGRFTISRDNSKNTLYLQ
PRLLIYGAATRATGIPARFSGSG MNSLRAEDTAVYYCARDIAIFGVVPDYWGQGTLVTVSSASTK
SGTEFTLTISSLQSEDFAVYYCQ GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALT
QYNNWPLTFGGGTKVEIKRTV SGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN
AA AAPSVFIFPPSDEQLKSGTASVV TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
CLLNNFYPREAKVQWKVDNAL MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCE
QSGNSQESVTEQDSKDSTYSLS EQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI
STLTLSKADYEKHKVYACEVT SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV
HQGLSSPVTKSFNRGEC
EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN
VFSCSVMHEALHNHYTQKSLSLSPGK
(SEQ ID NO: 186) (SEQ ID NO: 187)
GAAATAGTGATGACGCAGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCC
CCAGCCACCCTGTCTGTGTCT TGGGAGGTCCCTGAGACTCTCCTGTGCAGCATCTGGATTCA
CCAGGGGAAAGAGCCACCCT CCTTCAGTAACTATGGCATGCACTGGGTCCGCCAGGCTCCA
CTCCTGCAGGGCCAGTCAGAG GGCGAGGGGCTGGAGTGGGTGGCAGCTATATGGTTTGATGC
[hu anti- TGTTAGCAGCAACTTAGCCTG
AAGTGATAAATACTATGCAGACGCCGTGAAGGGCCGATTCA
<huGIPR> GTACCAGCAGAAACCTGGCC
CCATCTCCAGAGACAACTCCAAGAACACGCTGTATCTGCAA
2G10.647 AGGCTCCCAGGCTCCTCATCT
ATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTG
VK3 (1-236) ATGGTGCAGCCACCAGGGCC
TGCGAGAGATTTGGCGATTTTTGGAGTGGTCCCCGACTACT
VL]::huKLC ACTGGTATCCCAGCCAGGGTC
GGGGCCAGGGAACCCTGGTCACCGTGTCTAGTGCCTCCACC
-CL + AGTGGCAGTGGGTCTGGGAC
AAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAG
[Unknown AGAGTTCACTCTCACCATCAG
CACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGG
anti- NA CAGCCTGCAGTCTGAAGATTT
ACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGC
<huGIPR> TGCAGTTTATTACTGTCAGCA
GCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACA
2G10.610 GTATAATAACTGGCCTCTCAC
GTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGC
VH3 (1-472) TTTCGGCGGAGGGACCAAGGT
CCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTG
VH]::huIgG1 GGAGATCAAACGAACGGTGG
AATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTG
zSEFL2-2 CTGCACCATCTGTCTTCATCTT
AGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGC
(mAb); LMR CCCGCCATCTGATGAGCAGTT
CCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTC
ID: SS- GAAATCTGGAACTGCCTCTGT
CCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCC
1-3
2623 6 TGTGTGCCTGCTGAATAACTT
TGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACC
.7r CTATCCCAGAGAGGCCAAAG
CTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTG
`z. TACAGTGGAAGGTGGATAAC
CATAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCA
oe
GCCCTCCAATCGGGTAACTCC GCACGTACCGTTGCGTCAGCGTCCTCACCGTCCTGCACCAG
CAGGAGAGTGTCACAGAGCA GACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCCA
oe
oe
160
A-2164-WO-PCT
GGACAGCAAGGACAGCACCT ACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAA
ACAGCCTCAGCAGCACCCTGA GCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCC
CGCTGAGCAAAGCAGACTAC CCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTG
GAGAAACACAAAGTCTACGC ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGT
CTGCGAAGTCACCCATCAGGG GGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAG
CCTGAGCTCGCCCGTCACAAA ACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTC
GAGCTTCAACAGGGGAGAGT TATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGG
GT
GGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCAC
AACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAA
A
(SEQ ID NO: 188) (SEQ ID NO: 189)
EIVMTQ SP ATL SVSPGERATLS QVQLVE SGGGVVQPGRSLRL SCAASGFTFSNYGMHWVRQAP
CRASQ S VS SNLAWYQQKPGQA GEGLEWVAAIWFDASDKYYADAVKGRFTISRDNSKNTLYLQ
PRLLIYGAATRATGIPARVSGS MNSLRAEDTAVYYCARDLAIFGVVPDYWGQGTLVTVSSASTK
GS GTEFTL TI S SLQSEDFAVYYC GP SVFPL AP S SKST S GGTAALGCLVKDYFPEPVTVSWN S GAL
T
QQYNNWPLTFGGGTKVEIKRT SGVHTFPAVLQS SGLY SLS SVVTVP S S SLGTQTYICNVNHKP SN
AA VAAPSVFIFPPSDEQLKSGTASV TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
VCLLNNFYPREAKVQWKVDN MI SRTPEVTCVVVDVSHEDPEVKFNWYVD GVEVHNAKTKPCE
ALQSGNSQESVTEQDSKDSTYS EQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI
L SSTLTL SKADYEKHKVYACE SKAKGQPREPQVYTLPP SREEMTKNQVSLTCLVKGFYP SDIAV
VTHQGLSSPVTKSFNRGEC
EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN
VFSCSVMHEALHNHYTQKSLSLSPGK
(SEQ ID NO: 190) (SEQ ID NO: 191)
[hu anti- GAAATAGTGATGACGCAGTCT
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCC
<huGIPR> CCAGCCACCCTGTCTGTGTCT
TGGGAGGTCCCTGAGACTCTCCTGTGCAGCATCTGGATTCA
2G10.649 CCAGGGGAAAGAGCCACCCT
CCTTCAGTAACTATGGCATGCACTGGGTCCGCCAGGCTCCA
VK3 (1-236) CTCCTGCAGGGCCAGTCAGAG
GGCGAGGGGCTGGAGTGGGTGGCAGCTATATGGTTTGATGC
VL]::huKLC TGTTAGCAGCAACTTAGCCTG
AAGTGATAAATACTATGCAGACGCCGTGAAGGGCCGATTCA
-CL + [hu GTACCAGCAGAAACCTGGCC
CCATCTCCAGAGACAACTCCAAGAACACGCTGTATCTGCAA
anti- NA AGGCTCCCAGGCTCCTCATCT
ATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTG
<huGIPR> ATGAAGCAGCCACCAGGGCC
TGCGAGAGATCAGGCGATTTTTGGAGTGGTCCCCGATTACT 1-3
2G10.348 ACTGGTATCCCAGCCAGGGTC
GGGGCCAGGGAACCCTGGTCACCGTGTCTAGTGCCTCCACC
4 VH3 (1-472) AGTGGCAGTGGGTCTGGGAC
AAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAG
VH]::huIgG1 AGAGTTCACTCTCACCATCAG
CACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGG
zSEFL2-2 CAGCCTGCAGTCTGAAGATTT
ACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGC
(mAb); LMR TGCAGTTTATTACTGTCAGCA
GCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACA oe
oe
161
A-2164-WO-PCT
ID: SS- GTATAATAACTGGCCTCTCAC
GTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGC
2623 7 TTTCGGCGGAGGGACCAAGGT
CCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTG
GGAGATCAAACGAACGGTGG AATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTG
0
CTGCACCATCTGTCTTCATCTT AGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGC
n.)
o
CCCGCCATCTGATGAGCAGTT CCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTC
oe
i-J
GAAATCTGGAACTGCCTCTGT CCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCC
c,.)
--4
TGTGTGCCTGCTGAATAACTT TGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACC
o
vo
CTATCCCAGAGAGGCCAAAG CTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTG
--4
TACAGTGGAAGGTGGATAAC CATAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCA
GCCCTCCAATCGGGTAACTCC GCACGTACCGTTGCGTCAGCGTCCTCACCGTCCTGCACCAG
CAGGAGAGTGTCACAGAGCA GACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCCA
GGACAGCAAGGACAGCACCT ACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAA
ACAGCCTCAGCAGCACCCTGA GCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCC
CGCTGAGCAAAGCAGACTAC CCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTG
GAGAAACACAAAGTCTACGC ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGT
CTGCGAAGTCACCCATCAGGG GGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAG
P
CCTGAGCTCGCCCGTCACAAA ACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTC
o
GAGCTTCAACAGGGGAGAGT TATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGG
.
GT
GGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCAC ,
"
AACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAA
"
,
A
'
,
,
(SEQ ID NO: 192) (SEQ ID NO: 193)
.
,
EIVMTQSPATLSVSPGERATLS QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMHWVRQAP
,
CRASQSVSSNLAWYQQKPGQA GEGLEWVAAIWFDASDKYYADAVKGRFTISRDNSKNTLYLQ
PRLLIYEAATRATGIPARVSGSG MNSLRAEDTAVYYCARDQAIFGVVPDYWGQGTLVTVSSASTK
SGTEFTLTISSLQSEDFAVYYCQ GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALT
QYNNWPLTFGGGTKVEIKRTV SGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN
AAPSVFIFPPSDEQLKSGTASVV TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
AA
CLLNNFYPREAKVQWKVDNAL MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCE
QSGNSQESVTEQDSKDSTYSLS EQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI
00
STLTLSKADYEKHKVYACEVT SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV
n
1-3
HQGLSSPVTKSFNRGEC
EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN
cp
VFSCSVMHEALHNHYTQKSLSLSPGK
n.)
o
(SEQ ID NO: 194) (SEQ ID NO: 195)
oe
[hu anti-
NA GAAATAGTGATGACGCAGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCC
'a
" c= <huGIPR> CCAGCCACCCTGTCTGTGTCT
TGGGAGGTCCCTGAGACTCTCCTGTGCAGCATCTGGATTCA oe
c:
oe
162
A-2164-WO-PCT
2G10.305 CCAGGGGAAAGAGCCACCCT
CCTTCAGTAACTATGGCATGCACTGGGTCCGCCAGGCTCCA
VK3 (1-236) CTCCTGCAGGGCCAGTCAGAG
GGCGAGGGGCTGGAGTGGGTGGCAGCTATATGGTTTGATGC
VL]::huKLC TGTTGATGTTAACTTAGCCTG
AAGTGATAAATACTATGCAGACGCCGTGAAGGGCCGATTCA
-CL + GTACCAGCAGAAACCTGGCC
CCATCTCCAGAGACAACTCCAAGAACACGCTGTATCTGCAA
[Unknown AGGCTCCCAGGCTCCTCATCT
ATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTG
anti- ACAACGCAGCCACCAGGGCC
TGCGAGAGATTTGGCGATTTTTGGAGTGGTCCCCGACTACT
<huGIPR> ACTGGTATCCCAGCCAGGTTC
GGGGCCAGGGAACCCTGGTCACCGTGTCTAGTGCCTCCACC
2G10.610 AGTGGCAGTGGGTCTGGGAC
AAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAG
VH3 (1-472) AGAGTTCACTCTCACCATCAG
CACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGG
VH]::huIgG1 CAGCCTGCAGTCTGAAGATTT
ACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGC
zSEFL2-2 TGCAGTTTATTACTGTCAGCA
GCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACA
(mAb); LMR GTATCAGAACTGGCCTCTCAC
GTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGC
ID: SS- TTTCGGCGGAGGGACCAAGGT
CCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTG
26182 GGAGATCAAACGAACGGTGG
AATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTG
CTGCACCATCTGTCTTCATCTT AGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGC
CCCGCCATCTGATGAGCAGTT CCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTC
GAAATCTGGAACTGCCTCTGT CCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCC
TGTGTGCCTGCTGAATAACTT TGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACC
CTATCCCAGAGAGGCCAAAG CTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTG
TACAGTGGAAGGTGGATAAC CATAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCA
GCCCTCCAATCGGGTAACTCC GCACGTACCGTTGCGTCAGCGTCCTCACCGTCCTGCACCAG
CAGGAGAGTGTCACAGAGCA GACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCCA
GGACAGCAAGGACAGCACCT ACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAA
ACAGCCTCAGCAGCACCCTGA GCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCC
CGCTGAGCAAAGCAGACTAC CCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTG
GAGAAACACAAAGTCTACGC ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGT
CTGCGAAGTCACCCATCAGGG GGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAG
CCTGAGCTCGCCCGTCACAAA ACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTC
GAGCTTCAACAGGGGAGAGT TATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGG
GT
GGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCAC
AACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAA
1-3
A
(SEQ ID NO: 196) (SEQ ID NO: 197)
EIVMTQSPATLSVSPGERATLS QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMHWVRQAP
oe
AA CRASQSVDVNLAWYQQKPGQ GEGLEWVAAIWFDASDKYYADAVKGRFTISRDNSKNTLYLQ
APRLLIYNAATRATGIPARFSGS MNSLRAEDTAVYYCARDLAIFGVVPDYWGQGTLVTVSSASTK
oe
oe
163
A-2164-WO-PCT
GSGTEFTLTISSLQSEDFAVYYC GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALT
QQYQNWPLTFGGGTKVEIKRT SGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN
VAAPSVFIFPPSDEQLKSGTASV TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
VCLLNNFYPREAKVQWKVDN MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCE
ALQSGNSQESVTEQDSKDSTYS EQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI
LSSTLTLSKADYEKHKVYACE SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV
VTHQGLSSPVTKSFNRGEC
EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN
VFSCSVMHEALHNHYTQKSLSLSPGK
(SEQ ID NO: 198) (SEQ ID NO: 199)
GAAATAGTGATGACGCAGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCC
CCAGCCACCCTGTCTGTGTCT TGGGAGGTCCCTGAGACTCTCCTGTGCAGCATCTGGATTCA
CCAGGGGAAAGAGCCACCCT CCTTCAGTAACTATGGCATGCACTGGGTCCGCCAGGCTCCA
CTCCTGCAGGGCCAGTCAGAG GGCGAGGGGCTGGAGTGGGTGGCAGCTATATGGTTTGATGC
TGTTGATGTTAACTTAGCCTG AAGTGATAAATACTATGCAGACGCCGTGAAGGGCCGATTCA
h GTACCAGCAGAAACCTGGCC
CCATCTCCAGAGACAACTCCAAGAACACGCTGTATCTGCAA
R>
[u anti-
AGGCTCCCAGGCTCCTCATCT ATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTG
<huGIP
2G10.605 ACAACGCAGCCACCAGGGCC
TGCGAGAGATTTGGCGATTTTTGGAGTGGTCCCCGACTACT
ACTGGTATCCCAGCCAGGGTC GGGGCCAGGGAACCCTGGTCACCGTGTCTAGTGCCTCCACC
VK3 (1-236)
AGTGGCAGTGGGTCTGGGAC AAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAG
VL]::huKLC
AGAGTTCACTCTCACCATCAG CACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGG
-CL +
CAGCCTGCAGTCTGAAGATTT ACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGC
[Unknown
TGCAGTTTATTACTGTCAGCA GCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACA
anti-
NA GTATCAGAACTGGCCTCTCAC GTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGC
<huGIPR>
TTTCGGCGGAGGGACCAAGGT CCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTG
2G10.610
GGAGATCAAACGAACGGTGG AATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTG
VH3 :huIgG1(1-472)
CTGCACCATCTGTCTTCATCTT AGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGC
VH]:
SEFL2 CCCGCCATCTGATGAGCAGTT
CCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTC
-2
z
GAAATCTGGAACTGCCTCTGT CCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCC
(mAb); LMR
TGTGTGCCTGCTGAATAACTT TGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACC
ID: 26230 SS-
CTATCCCAGAGAGGCCAAAG CTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTG
TACAGTGGAAGGTGGATAAC CATAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCA
1-3
GCCCTCCAATCGGGTAACTCC GCACGTACCGTTGCGTCAGCGTCCTCACCGTCCTGCACCAG
CAGGAGAGTGTCACAGAGCA GACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCCA
`z. GGACAGCAAGGACAGCACCT
ACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAA
oe
ACAGCCTCAGCAGCACCCTGA GCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCC
CGCTGAGCAAAGCAGACTAC CCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTG
oe
oe
164
A-2164-WO-PCT
GAGAAACACAAAGTCTACGC ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGT
CTGCGAAGTCACCCATCAGGG GGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAG
CCTGAGCTCGCCCGTCACAAA ACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTC
GAGCTTCAACAGGGGAGAGT TATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGG
GT
GGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCAC
AACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAA
A
(SEQ ID NO: 200) (SEQ ID NO: 201)
EIVMTQSPATL SVSPGERATLS QVQLVE SGGGVVQPGRSLRL SCAASGFTFSNYGMHWVRQAP
CRASQSVDVNLAWYQQKPGQ GEGLEWVAAIWFDASDKYYADAVKGRFTISRDNSKNTLYLQ
APRLLIYNAATRATGIPARVSG MNSLRAEDTAVYYCARDLAIFGVVPDYWGQGTLVTVSSASTK
S GS GTEFTL TI S SLQ SEDFAVYY GP SVFPL AP S SKST S GGTAALGCLVKDYFPEPVTVSWN S
GAL T
CQQYQNWPLTFGGGTKVEIKR SGVHTFPAVLQSSGLY SLSSVVTVP SSSLGTQTYICNVNHKP SN
TVAAP SVFIFPP SDEQLKSGTAS TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
AA
VVCLLNNFYPREAKVQWKVD MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCE
NALQSGNSQESVTEQDSKDST EQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI
YSL SSTLTL SKADYEKHKVYA SKAKGQPREPQVYTLPP SREEMTKNQVSLTCLVKGFYP SDIAV
CEVTHQGL SSPVTKSFNRGEC EWE SNGQPENNYKTTPPVLD SD GSFFLY SKL TVD KSRWQQ GN
VFSCSVMHEALHNHYTQKSLSLSPGK
(SEQ ID NO: 202) (SEQ ID NO: 203)
h GAAATAGTGATGACGCAGTCT
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCC
[u anti-
CCAGCCACCCTGTCTGTGTCT TGGGAGGTCCCTGAGACTCTCCTGTGCAGCATCTGGATTCA
<huGIPR>
CCAGGGGAAAGAGCCACCCT CCTTCAGTAACTATGGCATGCACTGGGTCCGCCAGGCTCCA
2G10.340
VK3 1236)
CTCCTGCAGGGCCAGTCAGAG GGCGAGGGGCTGGAGTGGGTGGCAGCTATATGGTTTGATGC
(-
TGTTCATACGAACTTAGCCTG AAGTGATAAATACTATGCAGACGCCGTGAAGGGCCGATTCA
VL]::huKLC
GTACCAGCAGAAACCTGGCC CCATCTCCAGAGACAACTCCAAGAACACGCTGTATCTGCAA
-CL + [hu
AGGCTCCCAGGCTCCTCATCT ATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTG
anti-
ACAACGCAGCCACCAGGGCC TGCGAGAGATATTGCGATTTTTGGAGTGGTCCCCGACTACT
<huGIPR> NA
ACTGGTATCCCAGCCAGGTTC GGGGCCAGGGAACCCTGGTCACCGTGTCTAGTGCCTCCACC
2G10.325
VH3 1 472)
AGTGGCAGTGGGTCTGGGAC AAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAG
(
AGAGTTCACTCTCACCATCAG CACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGG
1-3
VH]: -
:huIgG1
CAGCCTGCAGTCTGAAGATTT ACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGC
zSEFL=2-2
TGCAGTTTATTACTGTCAGCA GCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACA
(mAb); LMR
GTATCAGAACTGGCCTCTCAC GTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGC
Itc: ID: SS-
oe
TTTCGGCGGAGGGACCAAGGT CCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTG
==.?1 26217
GGAGATCAAACGAACGGTGG AATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTG
oe
oe
165
A-2164-WO-PCT
CTGCACCATCTGTCTTCATCTT AGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGC
CCCGCCATCTGATGAGCAGTT CCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTC
GAAATCTGGAACTGCCTCTGT CCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCC
TGTGTGCCTGCTGAATAACTT TGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACC
CTATCCCAGAGAGGCCAAAG CTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTG
TACAGTGGAAGGTGGATAAC CATAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCA
GCCCTCCAATCGGGTAACTCC GCACGTACCGTTGCGTCAGCGTCCTCACCGTCCTGCACCAG
CAGGAGAGTGTCACAGAGCA GACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCCA
GGACAGCAAGGACAGCACCT ACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAA
ACAGCCTCAGCAGCACCCTGA GCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCC
CGCTGAGCAAAGCAGACTAC CCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTG
GAGAAACACAAAGTCTACGC ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGT
CTGCGAAGTCACCCATCAGGG GGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAG
CCTGAGCTCGCCCGTCACAAA ACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTC
GAGCTTCAACAGGGGAGAGT TATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGG
GT
GGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCAC
AACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAA
A
(SEQ ID NO: 204) (SEQ ID NO: 205)
EIVMTQSPATLSVSPGERATLS QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMHWVRQAP
CRASQSVHTNLAWYQQKPGQ GEGLEWVAAIWFDASDKYYADAVKGRFTISRDNSKNTLYLQ
APRLLIYNAATRATGIPARFSGS MNSLRAEDTAVYYCARDIAIFGVVPDYWGQGTLVTVSSASTK
GSGTEFTLTISSLQSEDFAVYYC GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALT
QQYQNWPLTFGGGTKVEIKRT SGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN
AA VAAPSVFIFPPSDEQLKSGTASV TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
VCLLNNFYPREAKVQWKVDN MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCE
ALQSGNSQESVTEQDSKDSTYS EQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI
LSSTLTLSKADYEKHKVYACE SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV
VTHQGLSSPVTKSFNRGEC
EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN
VFSCSVMHEALHNHYTQKSLSLSPGK
(SEQ ID NO: 206) (SEQ ID NO: 207)
1-3
[hu anti- GAAATAGTGATGACGCAGTCT
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCC
<huGIPR> CCAGCCACCCTGTCTGTGTCT
TGGGAGGTCCCTGAGACTCTCCTGTGCAGCATCTGGATTCA
re)
2G10.334 NA CCAGGGGAAAGAGCCACCCT
CCTTCAGTAACTATGGCATGCACTGGGTCCGCCAGGCTCCA
VK3 (1-236) CTCCTGCAGGGCCAGTCAGAG
GGCGAGGGGCTGGAGTGGGTGGCAGCTATATGGTTTGATGC
VL]::huKLC TGTTAACCTGAACTTAGCCTG
AAGTGATAAATACTATGCAGACGCCGTGAAGGGCCGATTCA oe
oe
166
A-2164-WO-PCT
-CL + GTACCAGCAGAAACCTGGCC
CCATCTCCAGAGACAACTCCAAGAACACGCTGTATCTGCAA
[Unknown AGGCTCCCAGGCTCCTCATCT
ATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTG
anti- ACCAGGCAGCCACCAGGGCC
TGCGAGAGATTTGGCGATTTTTGGAGTGGTCCCCGACTACT
<huGIPR> ACTGGTATCCCAGCCAGGTTC
GGGGCCAGGGAACCCTGGTCACCGTGTCTAGTGCCTCCACC
2G10.610 AGTGGCAGTGGGTCTGGGAC
AAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAG
VH3 (1-472) AGAGTTCACTCTCACCATCAG
CACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGG
VH]::huIgG1 CAGCCTGCAGTCTGAAGATTT
ACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGC
zSEFL2-2 TGCAGTTTATTACTGTCAGCA
GCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACA
(mAb); LMR GTATAACCAGTGGCCTCTCAC
GTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGC
ID: SS- TTTCGGCGGAGGGACCAAGGT
CCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTG
26211 GGAGATCAAACGAACGGTGG
AATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTG
CTGCACCATCTGTCTTCATCTT AGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGC
CCCGCCATCTGATGAGCAGTT CCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTC
GAAATCTGGAACTGCCTCTGT CCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCC
TGTGTGCCTGCTGAATAACTT TGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACC
CTATCCCAGAGAGGCCAAAG CTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTG
TACAGTGGAAGGTGGATAAC CATAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCA
GCCCTCCAATCGGGTAACTCC GCACGTACCGTTGCGTCAGCGTCCTCACCGTCCTGCACCAG
CAGGAGAGTGTCACAGAGCA GACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCCA
GGACAGCAAGGACAGCACCT ACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAA
ACAGCCTCAGCAGCACCCTGA GCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCC
CGCTGAGCAAAGCAGACTAC CCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTG
GAGAAACACAAAGTCTACGC ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGT
CTGCGAAGTCACCCATCAGGG GGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAG
CCTGAGCTCGCCCGTCACAAA ACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTC
GAGCTTCAACAGGGGAGAGT TATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGG
GT
GGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCAC
AACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAA
A
(SEQ ID NO: 208) (SEQ ID NO: 209)
EIVMTQSPATLSVSPGERATLS QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMHWVRQAP
1-3
CRASQSVNLNLAWYQQKPGQ GEGLEWVAAIWFDASDKYYADAVKGRFTISRDNSKNTLYLQ
AA APRLLIYQAATRATGIPARFSGS MNSLRAEDTAVYYCARDLAIFGVVPDYWGQGTLVTVSSASTK
GSGTEFTLTISSLQSEDFAVYYC GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALT
oe
QQYNQWPLTFGGGTKVEIKRT SGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN
VAAPSVFIFPPSDEQLKSGTASV TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
oe
oe
167
A-2164-WO-PCT
VCLLNNFYPREAKVQWKVDN MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCE
ALQSGNSQESVTEQDSKDSTYS EQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI
LSSTLTLSKADYEKHKVYACE SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV
VTHQGLSSPVTKSFNRGEC
EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN
VFSCSVMHEALHNHYTQKSLSLSPGK
(SEQ ID NO: 210) (SEQ ID NO: 211)
GAAATAGTGATGACGCAGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCC
CCAGCCACCCTGTCTGTGTCT TGGGAGGTCCCTGAGACTCTCCTGTGCAGCATCTGGATTCA
CCAGGGGAAAGAGCCACCCT CCTTCAGTAACTATGGCATGCACTGGGTCCGCCAGGCTCCA
CTCCTGCAGGGCCAGTCAGAG GGCGAGGGGCTGGAGTGGGTGGCAGCTATATGGTTTGATGC
TGTTTTCCAGAACTTAGCCTG AAGTGATAAATACTATGCAGACGCCGTGAAGGGCCGATTCA
GTACCAGCAGAAACCTGGCC CCATCTCCAGAGACAACTCCAAGAACACGCTGTATCTGCAA
AGGCTCCCAGGCTCCTCATCT ATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTG
h ACCAGGCAGCCACCAGGGCC
TGCGAGAGATATTGCGATTTTTGGAGTGGTCCCCGACTACT
R>
[u anti-
ACTGGTATCCCAGCCAGGTTC GGGGCCAGGGAACCCTGGTCACCGTGTCTAGTGCCTCCACC
<huGIP
2G10.339 AGTGGCAGTGGGTCTGGGAC
AAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAG
VK3 1 -236)
AGAGTTCACTCTCACCATCAG CACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGG
(
CAGCCTGCAGTCTGAAGATTT ACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGC
VL]::huKLC
TGCAGTTTATTACTGTCAGCA GCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACA
-CL + [hu
GTATAACCAGTGGCCTCTCAC GTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGC
anti-
TTTCGGCGGAGGGACCAAGGT CCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTG
<huGIPR> NA
GGAGATCAAACGAACGGTGG AATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTG
2G10.325
CTGCACCATCTGTCTTCATCTT AGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGC
VH3 :huIgG1(1-472)
CCCGCCATCTGATGAGCAGTT CCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTC
VH]:
SEFL2 GAAATCTGGAACTGCCTCTGT
CCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCC
z-2
Ab LMR TGTGTGCCTGCTGAATAACTT
TGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACC
(m);
SS CTATCCCAGAGAGGCCAAAG
CTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTG
-
ID:
TACAGTGGAAGGTGGATAAC CATAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCA
26216
GCCCTCCAATCGGGTAACTCC GCACGTACCGTTGCGTCAGCGTCCTCACCGTCCTGCACCAG
CAGGAGAGTGTCACAGAGCA GACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCCA
GGACAGCAAGGACAGCACCT ACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAA
1-3
ACAGCCTCAGCAGCACCCTGA GCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCC
CGCTGAGCAAAGCAGACTAC CCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTG
GAGAAACACAAAGTCTACGC ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGT
oe
CTGCGAAGTCACCCATCAGGG GGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAG
CCTGAGCTCGCCCGTCACAAA ACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTC
oe
oe
168
A-2164-WO-PCT
GAGCTTCAACAGGGGAGAGT TATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGG
GT
GGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCAC
AACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAA
A
(SEQ ID NO: 212) (SEQ ID NO: 213)
oe
EIVMTQ SP ATL SVSPGERATLS QVQLVE SGGGVVQPGRSLRL SCAASGFTFSNYGMHWVRQAP
CRASQSVFQNLAWYQQKPGQ GEGLEWVAAIWFDASDKYYADAVKGRFTISRDNSKNTLYLQ
APRLLIYQAATRATGIPARFSGS MNSLRAEDTAVYYCARDIAIFGVVPDYWGQGTLVTVSSASTK
GS GTEFTL TI S SLQSEDFAVYYC GP SVFPL AP S SKST S GGTAALGCL VKDYFPEPVTVSWN S
GAL T
QQYNQWPLTFGGGTKVEIKRT SGVHTFPAVLQS SGLY SLS SVVTVP S S SLGTQTYICNVNHKP SN
VAAPSVFIFPPSDEQLKSGTASV TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
AA
VCLLNNFYPREAKVQWKVDN MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCE
ALQSGNSQESVTEQD SKD STY S EQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI
L SSTLTL SKADYEKHKVYACE SKAKGQPREPQVYTLPP SREEMTKNQVSLTCLVKGFYP SDIAV
VTHQGLSSPVTKSFNRGEC EWE SNGQPENNYKTTPPVLD SD
GSFFLY SKL TVD KSRWQQ GN
VFSCSVMHEALHNHYTQKSLSLSPGK
(SEQ ID NO: 214) (SEQ ID NO: 215)
GAAATAGTGATGACGCAGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCC
CCAGCCACCCTGTCTGTGTCT TGGGAGGTCCCTGAGACTCTCCTGTGCAGCATCTGGATTCA
[hu anti- CCAGGGGAAAGAGCCACCCT
CCTTCCAGAACTATGGCATGCACTGGGTCCGCCAGGCTCCA
<huGIPR> CTCCTGCAGGGCCAGTCAGAG
GGCGAGGGGCTGGAGTGGGTGGCAGCTATATGGTTTGATGC
2G10.307 TGTTGATAGACACTTAGCCTG
GTACGGTAAATACTATGCAGACGCCGTGAAGGGCCGATTCA
VK3 (1-236) GTACCAGCAGAAACCTGGCC
CCATCTCCAGAGACAACTCCAAGAACACGCTGTATCTGCAA
VL]::huKLC AGGCTCCCAGGCTCCTCATCT
ATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTG
-CL + [hu ACGAAGCAGCCACCAGGGCC
TGCGAGAGATCAGACGATTTTTGGAGTGGTCCCCGACTACT
anti- ACTGGTATCCCAGCCAGGTTC
GGGGCCAGGGAACCCTGGTCACCGTGTCTAGTGCCTCCACC
<huGIPR> NA AGTGGCAGTGGGTCTGGGAC AAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAG
2G10.307 AGAGTTCACTCTCACCATCAG
CACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGG
VH3 (1-472) CAGCCTGCAGTCTGAAGATTT
ACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGC
VH]::huIgG1 TGCAGTTTATTACTGTCAGCA
GCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACA
zSEFL2-2 GTATAACCAGTGGCCTCTCAC
GTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGC 1-3
(mAb); LMR TTTCGGCGGAGGGACCAAGGT
CCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTG
6 ID: SS- GGAGATCAAACGAACGGTGG
AATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTG
re)
c5 26184 CTGCACCATCTGTCTTCATCTT
AGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGC
oe
CCCGCCATCTGATGAGCAGTT CCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTC
GAAATCTGGAACTGCCTCTGT CCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCC
oe
oe
169
A-2164-WO-PCT
TGTGTGCCTGCTGAATAACTT TGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACC
CTATCCCAGAGAGGCCAAAG CTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTG
TACAGTGGAAGGTGGATAAC CATAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCA
GCCCTCCAATCGGGTAACTCC GCACGTACCGTTGCGTCAGCGTCCTCACCGTCCTGCACCAG
CAGGAGAGTGTCACAGAGCA GACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCCA
GGACAGCAAGGACAGCACCT ACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAA
ACAGCCTCAGCAGCACCCTGA GCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCC
CGCTGAGCAAAGCAGACTAC CCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTG
GAGAAACACAAAGTCTACGC ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGT
CTGCGAAGTCACCCATCAGGG GGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAG
CCTGAGCTCGCCCGTCACAAA ACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTC
GAGCTTCAACAGGGGAGAGT TATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGG
GT
GGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCAC
AACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAA
A
(SEQ ID NO: 216) (SEQ ID NO: 217)
EIVMTQSPATL SVSPGERATLS QVQLVE SGGGVVQPGRSLRL SCAASGFTFQNYGMHWVRQAP
CRASQSVDRHLAWYQQKPGQ GEGLEWVAAIWFDAYGKYYADAVKGRFTISRDNSKNTLYLQ
APRLLIYEAATRATGIPARFSGS MNSLRAEDTAVYYCARDQTIFGVVPDYWGQGTLVTVSSASTK
GS GTEFTL TI S SLQ SEDFAVYYC GP SVFPL AP S SKST S GGTAALGCLVKDYFPEPVTVSWN S
GAL T
QQYNQWPLTFGGGTKVEIKRT SGVHTFPAVLQSSGLY SLSSVVTVP SSSLGTQTYICNVNHKP SN
AA VAAPSVFIFPPSDEQLKSGTASV TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
VCLLNNFYPREAKVQWKVDN MI SRTPEVTCVVVDVSHEDPEVKFNWYVD GVEVHNAKTKPCE
ALQSGNSQESVTEQD SKD STY S EQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI
L SSTLTL SKADYEKHKVYACE SKAKGQPREPQVYTLPP SREEMTKNQVSLTCLVKGFYP SDIAV
VTHQGLSSPVTKSFNRGEC EWE SNGQPENNYKTTPPVLD SD
GSFFLY SKL TVD KSRWQQ GN
VFSCSVMHEALHNHYTQKSLSLSPGK
(SEQ ID NO: 218) (SEQ ID NO: 219)
[hu anti- GAAATAGTGATGACGCAGTCT
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCC
<huGIPR> CCAGCCACCCTGTCTGTGTCT
TGGGAGGTCCCTGAGACTCTCCTGTGCAGCATCTGGATTCA
2G10.607 CCAGGGGAAAGAGCCACCCT
CCTTCCAGAACTATGGCATGCACTGGGTCCGCCAGGCTCCA 1-3
VK3 (1-236) CTCCTGCAGGGCCAGTCAGAG
GGCGAGGGGCTGGAGTGGGTGGCAGCTATATGGTTTGATGC
VL]::huKLC NA
TGTTGATAGACACTTAGCCTG GTACGGTAAATACTATGCAGACGCCGTGAAGGGCCGATTCA
-CL + [hu GTACCAGCAGAAACCTGGCC
CCATCTCCAGAGACAACTCCAAGAACACGCTGTATCTGCAA
anti- AGGCTCCCAGGCTCCTCATCT
ATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTG
<huGIPR> ACGAAGCAGCCACCAGGGCC
TGCGAGAGATCAGACGATTTTTGGAGTGGTCCCCGACTACT oe
oe
170
A-2164-WO-PCT
2G10.307 ACTGGTATCCCAGCCAGGGTC
GGGGCCAGGGAACCCTGGTCACCGTGTCTAGTGCCTCCACC
VH3 (1-472) AGTGGCAGTGGGTCTGGGAC
AAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAG
VH]::huIgG1 AGAGTTCACTCTCACCATCAG
CACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGG
zSEFL2-2 CAGCCTGCAGTCTGAAGATTT
ACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGC
(mAb); LMR TGCAGTTTATTACTGTCAGCA
GCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACA
ID: SS- GTATAACCAGTGGCCTCTCAC
GTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGC
26232 TTTCGGCGGAGGGACCAAGGT
CCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTG
GGAGATCAAACGAACGGTGG AATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTG
CTGCACCATCTGTCTTCATCTT AGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGC
CCCGCCATCTGATGAGCAGTT CCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTC
GAAATCTGGAACTGCCTCTGT CCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCC
TGTGTGCCTGCTGAATAACTT TGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACC
CTATCCCAGAGAGGCCAAAG CTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTG
TACAGTGGAAGGTGGATAAC CATAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCA
GCCCTCCAATCGGGTAACTCC GCACGTACCGTTGCGTCAGCGTCCTCACCGTCCTGCACCAG
CAGGAGAGTGTCACAGAGCA GACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCCA
GGACAGCAAGGACAGCACCT ACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAA
ACAGCCTCAGCAGCACCCTGA GCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCC
CGCTGAGCAAAGCAGACTAC CCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTG
GAGAAACACAAAGTCTACGC ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGT
CTGCGAAGTCACCCATCAGGG GGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAG
CCTGAGCTCGCCCGTCACAAA ACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTC
GAGCTTCAACAGGGGAGAGT TATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGG
GT
GGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCAC
AACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAA
A
(SEQ ID NO: 220) (SEQ ID NO: 221)
EIVMTQSPATLSVSPGERATLS QVQLVESGGGVVQPGRSLRLSCAASGFTFQNYGMHWVRQAP
CRASQSVDRHLAWYQQKPGQ GEGLEWVAAIWFDAYGKYYADAVKGRFTISRDNSKNTLYLQ
APRLLIYEAATRATGIPARVSGS MNSLRAEDTAVYYCARDQTIFGVVPDYWGQGTLVTVSSASTK
GSGTEFTLTISSLQSEDFAVYYC GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALT
1-3
AA QQYNQWPLTFGGGTKVEIKRT SGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN
VAAPSVFIFPPSDEQLKSGTASV TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
VCLLNNFYPREAKVQWKVDN MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCE
oe
ALQSGNSQESVTEQDSKDSTYS EQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI
LSSTLTLSKADYEKHKVYACE SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV
oe
oe
171
A-2164-WO-PCT
VTHQGLSSPVTKSFNRGEC
EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN
VFSCSVMHEALHNHYTQKSLSLSPGK
(SEQ ID NO: 222) (SEQ ID NO: 223)
0
GAAATAGTGATGACGCAGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCC
CCAGCCACCCTGTCTGTGTCT TGGGAGGTCCCTGAGACTCTCCTGTGCAGCATCTGGATTCA
oe
CCAGGGGAAAGAGCCACCCT CCTTCCAGAACTATGGCATGCACTGGGTCCGCCAGGCTCCA
CTCCTGCAGGGCCAGTCAGAG GGCGAGGGGCTGGAGTGGGTGGCAGCTATATGGTTTGATGC
TGTTAACCGGCACTTAGCCTG GTACGGTAAATACTATGCAGACGCCGTGAAGGGCCGATTCA
GTACCAGCAGAAACCTGGCC CCATCTCCAGAGACAACTCCAAGAACACGCTGTATCTGCAA
AGGCTCCCAGGCTCCTCATCT ATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTG
ACGAAGCAGCCACCAGGGCC TGCGAGAGATAAGACGATTTTTGGAGTGGTCCCCGACTACT
ACTGGTATCCCAGCCAGGTTC GGGGCCAGGGAACCCTGGTCACCGTGTCTAGTGCCTCCACC
[hu anti- AGTGGCAGTGGGTCTGGGAC
AAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAG
<huGIPR> AGAGTTCACTCTCACCATCAG
CACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGG
2G10.321 CAGCCTGCAGTCTGAAGATTT
ACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGC
VK3 (1-236) TGCAGTTTATTACTGTCAGCA
GCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACA p
VL]::huKLC GTATAACCAGTGGCCTCTCAC
GTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGC
-CL + [hu TTTCGGCGGAGGGACCAAGGT
CCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTG
anti- GGAGATCAAACGAACGGTGG
AATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTG
<huGIPR> NA CTGCACCATCTGTCTTCATCTT
AGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGC
2G10.321 CCCGCCATCTGATGAGCAGTT
CCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTC
VH3 (1-472) GAAATCTGGAACTGCCTCTGT
CCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCC
VH]::huIgG1 TGTGTGCCTGCTGAATAACTT
TGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACC
zSEFL2-2 CTATCCCAGAGAGGCCAAAG
CTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTG
(mAb); LMR TACAGTGGAAGGTGGATAAC
CATAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCA
ID: SS- GCCCTCCAATCGGGTAACTCC
GCACGTACCGTTGCGTCAGCGTCCTCACCGTCCTGCACCAG
26198 CAGGAGAGTGTCACAGAGCA
GACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCCA
GGACAGCAAGGACAGCACCT ACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAA
ACAGCCTCAGCAGCACCCTGA GCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCC
CGCTGAGCAAAGCAGACTAC CCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTG
GAGAAACACAAAGTCTACGC ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGT
1-3
CTGCGAAGTCACCCATCAGGG GGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAG
CCTGAGCTCGCCCGTCACAAA ACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTC
GAGCTTCAACAGGGGAGAGT TATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGG
oe
GT
GGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCAC
AACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAA
oe
cr
oe
172
A-2164-WO-PCT
A
(SEQ ID NO: 224) (SEQ ID NO: 225)
EIVMTQSPATLSVSPGERATLS QVQLVESGGGVVQPGRSLRLSCAASGFTFQNYGMHWVRQAP
0
CRASQSVNRHLAWYQQKPGQ GEGLEWVAAIWFDAYGKYYADAVKGRFTISRDNSKNTLYLQ
APRLLIYEAATRATGIPARFSGS MNSLRAEDTAVYYCARDKTIFGVVPDYWGQGTLVTVSSASTK
oe
GSGTEFTLTISSLQSEDFAVYYC GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALT
QQYNQWPLTFGGGTKVEIKRT SGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN
AA VAAPSVFIFPPSDEQLKSGTASV TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
VCLLNNFYPREAKVQWKVDN MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCE
ALQSGNSQESVTEQDSKDSTYS EQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI
LSSTLTLSKADYEKHKVYACE SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV
VTHQGLSSPVTKSFNRGEC
EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN
VFSCSVMHEALHNHYTQKSLSLSPGK
(SEQ ID NO: 226) (SEQ ID NO: 227)
GAAATAGTGATGACGCAGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCC
CCAGCCACCCTGTCTGTGTCT TGGGAGGTCCCTGAGACTCTCCTGTGCAGCATCTGGATTCA
p
CCAGGGGAAAGAGCCACCCT CCTTCCAGAACTATGGCATGCACTGGGTCCGCCAGGCTCCA
CTCCTGCAGGGCCAGTCAGAG GGCGAGGGGCTGGAGTGGGTGGCAGCTATATGGTTTGATGC
[hu anti-
<huGIPR> TGTTGAAAGACACTTAGCCTG
GTACGGTAAATACTATGCAGACGCCGTGAAGGGCCGATTCA
2G10.342 GTACCAGCAGAAACCTGGCC
CCATCTCCAGAGACAACTCCAAGAACACGCTGTATCTGCAA
VK3
AGGCTCCCAGGCTCCTCATCT ATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTG
( 1-236)
VL ACGAAGCAGCCACCAGGGCC
TGCGAGAGATAAGACGATTTTTGGAGTGGTCCCCGACTACT
]
::huKLC
ACTGGTATCCCAGCCAGGTTC GGGGCCAGGGAACCCTGGTCACCGTGTCTAGTGCCTCCACC
-CL + [hu
AGTGGCAGTGGGTCTGGGAC AAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAG
NA
anti-
AGAGTTCACTCTCACCATCAG CACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGG
<huGIPR>
2G10.321 CAGCCTGCAGTCTGAAGATTT
ACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGC
VH3 1 472)
TGCAGTTTATTACTGTCAGCA GCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACA
- (
GTATCAGCAGTGGCCTCTCAC GTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGC
VH]::huIgG1
TTTCGGCGGAGGGACCAAGGT CCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTG
zSEFL2-2
GGAGATCAAACGAACGGTGG AATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTG
(mAb); LMR
CTGCACCATCTGTCTTCATCTT AGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGC
1-3
ID: 26219 SS-
CCCGCCATCTGATGAGCAGTT CCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTC
r,1
.7r GAAATCTGGAACTGCCTCTGT
CCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCC
TGTGTGCCTGCTGAATAACTT TGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACC
oe
CTATCCCAGAGAGGCCAAAG CTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTG
TACAGTGGAAGGTGGATAAC CATAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCA
oe
cr
oe
173
A-2164-WO-PCT
GCCCTCCAATCGGGTAACTCC GCACGTACCGTTGCGTCAGCGTCCTCACCGTCCTGCACCAG
CAGGAGAGTGTCACAGAGCA GACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCCA
GGACAGCAAGGACAGCACCT ACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAA
ACAGCCTCAGCAGCACCCTGA GCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCC
CGCTGAGCAAAGCAGACTAC CCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTG
GAGAAACACAAAGTCTACGC ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGT
CTGCGAAGTCACCCATCAGGG GGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAG
CCTGAGCTCGCCCGTCACAAA ACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTC
GAGCTTCAACAGGGGAGAGT TATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGG
GT
GGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCAC
AACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAA
A
(SEQ ID NO: 228) (SEQ ID NO: 229)
EIVMTQSPATLSVSPGERATLS QVQLVESGGGVVQPGRSLRLSCAASGFTFQNYGMHWVRQAP
CRASQSVERHLAWYQQKPGQ GEGLEWVAAIWFDAYGKYYADAVKGRFTISRDNSKNTLYLQ
APRLLIYEAATRATGIPARFSGS MNSLRAEDTAVYYCARDKTIFGVVPDYWGQGTLVTVSSASTK
GSGTEFTLTISSLQSEDFAVYYC GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALT
QQYQQWPLTFGGGTKVEIKRT SGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN
VAAPSVFIFPPSDEQLKSGTASV TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
AA
VCLLNNFYPREAKVQWKVDN MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCE
ALQSGNSQESVTEQDSKDSTYS EQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI
LSSTLTLSKADYEKHKVYACE SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV
VTHQGLSSPVTKSFNRGEC
EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN
VFSCSVMHEALHNHYTQKSLSLSPGK
(SEQ ID NO: 230) (SEQ ID NO: 231)
[hu anti- GAAATAGTGATGACGCAGTCT
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCC
<huGIPR> CCAGCCACCCTGTCTGTGTCT
TGGGAGGTCCCTGAGACTCTCCTGTGCAGCATCTGGATTCA
2G10.316 CCAGGGGAAAGAGCCACCCT
CCTTCAGTAACTATGGCATGCACTGGGTCCGCCAGGCTCCA
VK3 (1-236) CTCCTGCAGGGCCAGTCAGAG
GGCGAGGGGCTGGAGTGGGTGGCAGCTATATGGTTTGATGC
VL]::huKLC TGTTTTCAGACACTTAGCCTG
GTACGGTAAATACTATGCAGACGCCGTGAAGGGCCGATTCA
-CL + [hu NA GTACCAGCAGAAACCTGGCC
CCATCTCCAGAGACAACTCCAAGAACACGCTGTATCTGCAA 1-
3
anti- AGGCTCCCAGGCTCCTCATCT
ATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTG
<huGIPR> ACGAAGCAGCCACCAGGGCC
TGCGAGAGATAAGACGATTTTTGGAGTGGTCCCCGACTACT
re)
2G10.319 ACTGGTATCCCAGCCAGGTTC
GGGGCCAGGGAACCCTGGTCACCGTGTCTAGTGCCTCCACC
VH3 (1-472) AGTGGCAGTGGGTCTGGGAC
AAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAG
VH]::huIgG1 AGAGTTCACTCTCACCATCAG
CACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGG oe
oe
174
A-2164-WO-PCT
zSEFL2-2 CAGCCTGCAGTCTGAAGATTT
ACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGC
(mAb); LMR TGCAGTTTATTACTGTCAGCA
GCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACA
ID: SS- GTATCAGAACTGGCCTCTCAC
GTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGC
26196 TTTCGGCGGAGGGACCAAGGT
CCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTG
GGAGATCAAACGAACGGTGG AATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTG
CTGCACCATCTGTCTTCATCTT AGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGC
CCCGCCATCTGATGAGCAGTT CCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTC
GAAATCTGGAACTGCCTCTGT CCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCC
TGTGTGCCTGCTGAATAACTT TGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACC
CTATCCCAGAGAGGCCAAAG CTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTG
TACAGTGGAAGGTGGATAAC CATAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCA
GCCCTCCAATCGGGTAACTCC GCACGTACCGTTGCGTCAGCGTCCTCACCGTCCTGCACCAG
CAGGAGAGTGTCACAGAGCA GACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCCA
GGACAGCAAGGACAGCACCT ACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAA
ACAGCCTCAGCAGCACCCTGA GCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCC
CGCTGAGCAAAGCAGACTAC CCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTG
GAGAAACACAAAGTCTACGC ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGT
CTGCGAAGTCACCCATCAGGG GGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAG
CCTGAGCTCGCCCGTCACAAA ACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTC
GAGCTTCAACAGGGGAGAGT TATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGG
GT
GGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCAC
AACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAA
A
(SEQ ID NO: 232) (SEQ ID NO: 233)
EIVMTQSPATLSVSPGERATLS QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMHWVRQAP
CRASQSVFRHLAWYQQKPGQA GEGLEWVAAIWFDAYGKYYADAVKGRFTISRDNSKNTLYLQ
PRLLIYEAATRATGIPARFSGSG MNSLRAEDTAVYYCARDKTIFGVVPDYWGQGTLVTVSSASTK
SGTEFTLTISSLQSEDFAVYYCQ GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALT
QYQNWPLTFGGGTKVEIKRTV SGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN
AA AAPSVFIFPPSDEQLKSGTASVV TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
CLLNNFYPREAKVQWKVDNAL MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCE
1-3
QSGNSQESVTEQDSKDSTYSLS EQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI
STLTLSKADYEKHKVYACEVT SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV
HQGLSSPVTKSFNRGEC
EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN
oe
VFSCSVMHEALHNHYTQKSLSLSPGK
(SEQ ID NO: 234) (SEQ ID NO: 235)
oe
oe
175
A-2164-WO-PCT
GAAATAGTGATGACGCAGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCC
CCAGCCACCCTGTCTGTGTCT TGGGAGGTCCCTGAGACTCTCCTGTGCAGCATCTGGATTCA
CCAGGGGAAAGAGCCACCCT CCTTCCAGAACTATGGCATGCACTGGGTCCGCCAGGCTCCA
0
CTCCTGCAGGGCCAGTCAGAG GGCGAGGGGCTGGAGTGGGTGGCAGCTATATGGTTTGATGC
o
TGTTCTGAGTCACTTAGCCTG GTACGACAAATACTATGCAGACGCCGTGAAGGGCCGATTCA
oe
GTACCAGCAGAAACCTGGCC CCATCTCCAGAGACAACTCCAAGAACACGCTGTATCTGCAA
c,.)
-4
AGGCTCCCAGGCTCCTCATCT ATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTG
o
vo
ACGAAGCAGCCACCAGGGCC TGCGAGAGATAAGTCGATTTTTGGAGTGGTCCCCGACTACT
-4
ACTGGTATCCCAGCCAGGTTC GGGGCCAGGGAACCCTGGTCACCGTGTCTAGTGCCTCCACC
AGTGGCAGTGGGTCTGGGAC AAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAG
AGAGTTCACTCTCACCATCAG CACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGG
[hu anti-
CAGCCTGCAGTCTGAAGATTT ACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGC
<huGIPR>
TGCAGTTTATTACTGTCAGCA GCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACA
2G10.318
GTATAACAACTGGCCTCTCAC GTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGC
VK3 (1-236)
TTTCGGCGGAGGGACCAAGGT CCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTG
VL]::huKLC
GGAGATCAAACGAACGGTGG AATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTG
P
-CL + [hu
CTGCACCATCTGTCTTCATCTT AGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGC
o
anti-
,D
NA CCCGCCATCTGATGAGCAGTT CCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTC
.
<huGIPR>
,
GAAATCTGGAACTGCCTCTGT CCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCC
"
2G10.332
.
TGTGTGCCTGCTGAATAACTT TGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACC
"
,D
VH3 (1-472)
,
CTATCCCAGAGAGGCCAAAG CTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTG
' ,
VH]::huIgG1
,
TACAGTGGAAGGTGGATAAC CATAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCA
,
zSEFL2-2
GCCCTCCAATCGGGTAACTCC GCACGTACCGTTGCGTCAGCGTCCTCACCGTCCTGCACCAG
,
(mAb); LMR
CAGGAGAGTGTCACAGAGCA GACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCCA
ID: SS-
GGACAGCAAGGACAGCACCT ACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAA
26209
ACAGCCTCAGCAGCACCCTGA GCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCC
CGCTGAGCAAAGCAGACTAC CCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTG
GAGAAACACAAAGTCTACGC ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGT
CTGCGAAGTCACCCATCAGGG GGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAG
CCTGAGCTCGCCCGTCACAAA ACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTC
00
GAGCTTCAACAGGGGAGAGT TATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGG
n
1-3
GT
GGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCAC
AACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAA
cp
l=.)
re)
n A
_______________________________________________________________ o
o oe
Pi (SEQ ID NO: 236) (SEQ ID NO: 237)
-1
AA EIVMTQSPATLSVSPGERATLS QVQLVESGGGVVQPGRSLRLSCAASGFTFQNYGMHWVRQAP
oe
c:
oe
176
A-2164-WO-PCT
CRASQSVLSHLAWYQQKPGQA GEGLEWVAAIWFDAYDKYYADAVKGRFTISRDNSKNTLYLQ
PRLLIYEAATRATGIPARFSGSG MNSLRAEDTAVYYCARDKSIFGVVPDYWGQGTLVTVSSASTK
SGTEFTLTISSLQSEDFAVYYCQ GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALT
QYNNWPLTFGGGTKVEIKRTV SGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN
AAPSVFIFPPSDEQLKSGTASVV TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
CLLNNFYPREAKVQWKVDNAL MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCE
QSGNSQESVTEQDSKDSTYSLS EQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI
STLTLSKADYEKHKVYACEVT SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV
HQGLSSPVTKSFNRGEC
EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN
VFSCSVMHEALHNHYTQKSLSLSPGK
(SEQ ID NO: 238) (SEQ ID NO: 239)
GAAATAGTGATGACGCAGTCT CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCC
CCAGCCACCCTGTCTGTGTCT TGGGAGGTCCCTGAGACTCTCCTGTGCAGCATCTGGATTCA
CCAGGGGAAAGAGCCACCCT CCTTCCAGAACTATGGCATGCACTGGGTCCGCCAGGCTCCA
CTCCTGCAGGGCCAGTCAGAG GGCGAGGGGCTGGAGTGGGTGGCAGCTATATGGTTTGATGC
TGTTAACAGACACTTAGCCTG GTACGACAAATACTATGCAGACGCCGTGAAGGGCCGATTCA
[hu anti- GTACCAGCAGAAACCTGGCC
CCATCTCCAGAGACAACTCCAAGAACACGCTGTATCTGCAA
<huGIPR> AGGCTCCCAGGCTCCTCATCT
ATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTG
2G10.345 ACGAAGCAGCCACCAGGGCC
TGCGAGAGATAAGTCGATTTTTGGAGTGGTCCCCGACTACT
VK3 (1-236) ACTGGTATCCCAGCCAGGTTC
GGGGCCAGGGAACCCTGGTCACCGTGTCTAGTGCCTCCACC
VL]::huKLC AGTGGCAGTGGGTCTGGGAC
AAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAG
-CL + [hu AGAGTTCACTCTCACCATCAG
CACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGG
anti- CAGCCTGCAGTCTGAAGATTT
ACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGC
<huGIPR> NA TGCAGTTTATTACTGTCAGCA GCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACA
2G10.332 GTATAACAACTGGCCTCTCAC
GTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGC
VH3 (1-472) TTTCGGCGGAGGGACCAAGGT
CCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTG
VH]::huIgG1 GGAGATCAAACGAACGGTGG
AATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTG
zSEFL2-2 CTGCACCATCTGTCTTCATCTT
AGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGC
(mAb); LMR CCCGCCATCTGATGAGCAGTT
CCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTC
ID: SS- GAAATCTGGAACTGCCTCTGT
CCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCC
26222 TGTGTGCCTGCTGAATAACTT
TGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACC
1-3
CTATCCCAGAGAGGCCAAAG CTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTG
.7r TACAGTGGAAGGTGGATAAC
CATAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCA
GCCCTCCAATCGGGTAACTCC GCACGTACCGTTGCGTCAGCGTCCTCACCGTCCTGCACCAG
oe
CAGGAGAGTGTCACAGAGCA GACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCCA
GGACAGCAAGGACAGCACCT ACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAA
oe
oe
177
A-2164-WO-PCT
ACAGCCTCAGCAGCACCCTGA GCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCC
CGCTGAGCAAAGCAGACTAC CCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTG
GAGAAACACAAAGTCTACGC ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGT
CTGCGAAGTCACCCATCAGGG GGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAG
CCTGAGCTCGCCCGTCACAAA ACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTC
GAGCTTCAACAGGGGAGAGT TATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGG
GT
GGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCAC
AACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAA
A
(SEQ ID NO: 240) (SEQ ID NO: 241)
EIVMTQ SP ATL SVSPGERATLS QVQLVE SGGGVVQPGRSLRL SCAASGFTFQNYGMHWVRQAP
CRASQSVNRHLAWYQQKPGQ GEGLEWVAAIWFDAYDKYYADAVKGRFTISRDNSKNTLYLQ
APRLLIYEAATRATGIPARFSGS MNSLRAEDTAVYYCARDKSIFGVVPDYWGQGTLVTVSSASTK
GS GTEFTL TI S SLQSEDFAVYYC GP SVFPL AP S SKST S GGTAALGCLVKDYFPEPVTVSWN S GAL
T
QQYNNWPLTFGGGTKVEIKRT SGVHTFPAVLQS SGLY SLS SVVTVP S S SLGTQTYICNVNHKP SN
AA VAAPSVFIFPPSDEQLKSGTASV TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
VCLLNNFYPREAKVQWKVDN MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCE
ALQSGNSQESVTEQD SKD STY S EQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI
L SSTLTL SKADYEKHKVYACE SKAKGQPREPQVYTLPP SREEMTKNQVSLTCLVKGFYP SDIAV
VTHQGLSSPVTKSFNRGEC EWE SNGQPENNYKTTPPVLD SD
GSFFLY SKL TVD KSRWQQ GN
VFSCSVMHEALHNHYTQKSLSLSPGK
(SEQ ID NO: 242) (SEQ ID NO: 243)
[hu anti- GAAATAGTGATGACGCAGTCT
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCC
<huGIPR> CCAGCCACCCTGTCTGTGTCT
TGGGAGGTCCCTGAGACTCTCCTGTGCAGCATCTGGATTCA
2G10.335 CCAGGGGAAAGAGCCACCCT
CCTTCCAGAACTATGGCATGCACTGGGTCCGCCAGGCTCCA
VK3 (1-236) CTCCTGCAGGGCCAGTCAGAG
GGCGAGGGGCTGGAGTGGGTGGCAGCTATATGGTTTGATGC
VL]::huKLC TGTTACCAGCCACTTAGCCTG
GTACGACAAATACTATGCAGACGCCGTGAAGGGCCGATTCA
-CL + [hu GTACCAGCAGAAACCTGGCC
CCATCTCCAGAGACAACTCCAAGAACACGCTGTATCTGCAA
anti- NA AGGCTCCCAGGCTCCTCATCT
ATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTG
<huGIPR> ACGAAGCAGCCACCAGGGCC
TGCGAGAGATCTCGCGATTTTTGGAGTGGTCCCCGACTACT
2G10.335 ACTGGTATCCCAGCCAGGTTC
GGGGCCAGGGAACCCTGGTCACCGTGTCTAGTGCCTCCACC 1-3
VH3 (1-472) AGTGGCAGTGGGTCTGGGAC
AAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAG
VH]::huIgG1 AGAGTTCACTCTCACCATCAG
CACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGG
re)
Z SEFL2-2 CAGCCTGCAGTCTGAAGATTT
ACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGC
(mAb); LMR TGCAGTTTATTACTGTCAGCA
GCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACA
ID: SS- GTATAACCAGTGGCCTCTCAC
GTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGC oe
oe
178
A-2164-WO-PCT
26212 TTTCGGCGGAGGGACCAAGGT
CCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTG
GGAGATCAAACGAACGGTGG AATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTG
CTGCACCATCTGTCTTCATCTT AGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGC
0
CCCGCCATCTGATGAGCAGTT CCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTC
n.)
o
GAAATCTGGAACTGCCTCTGT CCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCC
oe
i-J
TGTGTGCCTGCTGAATAACTT TGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACC
c,.)
--.1
CTATCCCAGAGAGGCCAAAG CTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTG
o
vo
TACAGTGGAAGGTGGATAAC CATAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCA
--.1
GCCCTCCAATCGGGTAACTCC GCACGTACCGTTGCGTCAGCGTCCTCACCGTCCTGCACCAG
CAGGAGAGTGTCACAGAGCA GACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCCA
GGACAGCAAGGACAGCACCT ACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAA
ACAGCCTCAGCAGCACCCTGA GCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCC
CGCTGAGCAAAGCAGACTAC CCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTG
GAGAAACACAAAGTCTACGC ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGT
CTGCGAAGTCACCCATCAGGG GGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAG
CCTGAGCTCGCCCGTCACAAA ACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTC
P
GAGCTTCAACAGGGGAGAGT TATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGG
o
GT
GGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCAC .
AACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAA
,
'.
A
"
,
(SEQ ID NO: 244) (SEQ ID NO: 245)
' ,
,
EIVMTQSPATLSVSPGERATLS QVQLVESGGGVVQPGRSLRLSCAASGFTFQNYGMHWVRQAP
.
,
CRASQSVTSHLAWYQQKPGQA GEGLEWVAAIWFDAYDKYYADAVKGRFTISRDNSKNTLYLQ
,
PRLLIYEAATRATGIPARFSGSG MNSLRAEDTAVYYCARDLAIFGVVPDYWGQGTLVTVSSASTK
SGTEFTLTISSLQSEDFAVYYCQ GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALT
QYNQWPLTFGGGTKVEIKRTV SGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN
AA AAPSVFIFPPSDEQLKSGTASVV TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
CLLNNFYPREAKVQWKVDNAL MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCE
QSGNSQESVTEQDSKDSTYSLS EQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI
STLTLSKADYEKHKVYACEVT SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV
00
HQGLSSPVTKSFNRGEC
EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN n
1-3
VFSCSVMHEALHNHYTQKSLSLSPGK
cp
(SEQ ID NO: 246) (SEQ ID NO: 247)
n.)
o
c: [hu anti- GAAATAGTGATGACGCAGTCT
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCC
oe
,c1 <huGIPR> NA CCAGCCACCCTGTCTGTGTCT
TGGGAGGTCCCTGAGACTCTCCTGTGCAGCATCTGGATTCA 'a
2G10.330 CCAGGGGAAAGAGCCACCCT
CCTTCCAGAACTATGGCATGCACTGGGTCCGCCAGGCTCCA oe
c:
oe
179
A-2164-WO-PCT
VK3 (1-236) CTCCTGCAGGGCCAGTCAGAG
GGCGAGGGGCTGGAGTGGGTGGCAGCTATATGGTTTGATGC
VL]::huKLC TGTTGATCAGCACTTAGCCTG
GGCTTTCAAATACTATGCAGACGCCGTGAAGGGCCGATTCA
-CL + [hu GTACCAGCAGAAACCTGGCC
CCATCTCCAGAGACAACTCCAAGAACACGCTGTATCTGCAA
anti- AGGCTCCCAGGCTCCTCATCT
ATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTG
<huGIPR> ACCAGGCAGCCACCAGGGCC
TGCGAGAGATCTCGCGATTTTTGGAGTGGTCCCCGACTACT
2G10.330 ACTGGTATCCCAGCCAGGTTC
GGGGCCAGGGAACCCTGGTCACCGTGTCTAGTGCCTCCACC
VH3 (1-472) AGTGGCAGTGGGTCTGGGAC
AAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAG
VH]::huIgG1 AGAGTTCACTCTCACCATCAG
CACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGG
zSEFL2-2 CAGCCTGCAGTCTGAAGATTT
ACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGC
(mAb); LMR TGCAGTTTATTACTGTCAGCA
GCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACA
ID: SS- GTATCAGAACTGGCCTCTCAC
GTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGC
26207 TTTCGGCGGAGGGACCAAGGT
CCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTG
GGAGATCAAACGAACGGTGG AATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTG
CTGCACCATCTGTCTTCATCTT AGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGC
CCCGCCATCTGATGAGCAGTT CCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTC
GAAATCTGGAACTGCCTCTGT CCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCC
TGTGTGCCTGCTGAATAACTT TGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACC
CTATCCCAGAGAGGCCAAAG CTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTG
TACAGTGGAAGGTGGATAAC CATAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCA
GCCCTCCAATCGGGTAACTCC GCACGTACCGTTGCGTCAGCGTCCTCACCGTCCTGCACCAG
CAGGAGAGTGTCACAGAGCA GACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCCA
GGACAGCAAGGACAGCACCT ACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAA
ACAGCCTCAGCAGCACCCTGA GCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCC
CGCTGAGCAAAGCAGACTAC CCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTG
GAGAAACACAAAGTCTACGC ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGT
CTGCGAAGTCACCCATCAGGG GGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAG
CCTGAGCTCGCCCGTCACAAA ACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTC
GAGCTTCAACAGGGGAGAGT TATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGG
GT
GGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCAC
AACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAA
A
1-3
(SEQ ID NO: 248) (SEQ ID NO: 249)
EIVMTQSPATLSVSPGERATLS QVQLVESGGGVVQPGRSLRLSCAASGFTFQNYGMHWVRQAP
AA
CRASQSVDQHLAWYQQKPGQ GEGLEWVAAIWFDAAFKYYADAVKGRFTISRDNSKNTLYLQ
oe
APRLLIYQAATRATGIPARFSGS MNSLRAEDTAVYYCARDLAIFGVVPDYWGQGTLVTVSSASTK
GSGTEFTLTISSLQSEDFAVYYC GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALT
oe
oe
180
A-2164-WO-P CT
QQYQNWPLTFGGGTKVEIKRT SGVHTFPAVLQSSGLY SLSSVVTVP SSSLGTQTYICNVNHKP SN
VAAPSVFIFPPSDEQLKSGTASV TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
VCLLNNFYPREAKVQWKVDN MI SRTPEVTCVVVDVSHEDPEVKFNWYVD GVEVHNAKTKPCE
0
ALQSGNSQESVTEQDSKDSTYS EQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI
n.)
o
L SSTLTL SKADYEKHKVYACE SKAKGQPREPQVYTLPP SREEMTKNQVSLTCLVKGFYP SDIAV
oe
i-J
VTHQGLSSPVTKSFNRGEC
EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN c,.)
--.1
VFSCSVMHEALHNHYTQKSLSLSPGK
o
(SEQ ID NO: 250) (SEQ ID NO: 251)
--.1
ATGGACATGAGGGTGCCCGCT ATGGACATGAGGGTGCCCGCTCAGCTCCTGGGGCTCCTGCT
CAGCTCCTGGGGCTCCTGCTG GCTGTGGCTGAGAGGTGCGCGCTGTCAGGTGCAGCTGGTGG
CTGTGGCTGAGAGGTGCGCGC AGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGA
TGTGAAATCGTGATGACGCAG CTCTCCTGTGCAGCATCTGGATTCACCTTCAGTAACTATGGC
TCTCCAGCCACCCTGTCTGTG ATGCACTGGGTCCGCCAGGCTCCAGGCGAGGGGCTGGAGTG
TCTCCAGGGGAAAGAGCCAC GGTGGCAGCTATCTGGTTTGATGCAAGTGATAAATACTATG
CCTCTCCTGCAGGGCCAGTCA CAGACGCCGTGAAGGGCCGATTCACCATCTCCAGAGACAAC
GAGTGTTAGCGAACACTTAGC TCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGC
P
CTGGTACCAGCAGAAACCTG CGAGGACACGGCTGTGTATTACTGTGCGAGAGATCTGGCGA
L.
GCCAGGCTCCCAGGCTCCTCA TTTTTGGAGTGATTCCCGACTACTGGGGCCAGGGAACCCTG
.
,
TCTACGAAGCAGCCACCAGG GTCACCGTGTCTAGTGCCTCCACCAAGGGCCCATCGGTCTTC
..
GCCACTGGTATCCCAGCCAGG CCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGC
,-i
Go TTCAGTGGCAGTGGGTCTGGG
GGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGG
Lo':
re)
r
01 ACAGAGTTCACTCTCACCATC
TGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTG .
,
e'l NA
L.
in AGCAGCCTGCAGTCTGAAGAT
CACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCC ,
ci3
0.0 TTTGCAGTTTATTACTGTCAG
CTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCAC
¨
CAGTATCAGAACTGGCCTCTC CCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACA
ACTTTCGGCGGAGGGACCAA CCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAA
GGTGGAGATCAAACGAACGG ACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGG
TGGCTGCACCATCTGTCTTCA GGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACA
TCTTCCCGCCATCTGATGAGC CCCTCTACATCACCCGGGAGCCTGAGGTCACATGCGTGGTG
AGTTGAAATCTGGAACTGCCT GTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTG
00
CTGTTGTGTGCCTGCTGAATA GTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAG
n
1-3
ACTTCTATCCCAGAGAGGCCA CCGTGCGAGGAGCAGTACGGCAGCACGTACCGTTGCGTCAG
cp
AAGTACAGTGGAAGGTGGAT CGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGG
n.)
o
AACGCCCTCCAATCGGGTAAC AGTACAAGTGCAAGGTGTCCAACAAAGCCCTCCCAGCCCCC
oe
TCCCAGGAGAGTGTCACAGA ATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAG
'a
GCAGGACAGCAAGGACAGCA AACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATG
oe
cA
oe
181
A-2164-WO-PCT
CCTACAGCCTCAGCAGCACCC ACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTT
TGACGCTGAGCAAAGCAGAC CTATCCCAGCGATATCGCCGTGGAGTGGGAGAGCAATGGGC
TACGAGAAACACAAAGTCTA AGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGAC
0
n.)
CGCCTGCGAAGTCACCCATCA TCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGAC
o
GGGCCTGAGCTCGCCCGTCAC AAGAGTAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGT
oe
i-J
AAAGAGCTTCAACAGGGGAG GATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCC
c,.)
--.1
AGTGT TCTCCCTGTCTCCGGGTAAA
o
o
(SEQ ID NO: 1361 (SEQ ID NO: 1362
--.1
EIVMTQSPATL SVSPGERATLS QVQLVE SGGGVVQPGRSLRL SCAASGFTFSNYGMHWVRQAP
CRASQSVSEHLAWYQQKPGQA GEGLEWVAAIWFDASDKYYADAVKGRFTISRDNSKNTLYLQ
PRLLIYEAATRATGIPARFSGSG MNSLRAEDTAVYYCARDLAIFGVIPDYWGQGTLVTVSSASTK
SGTEFTLTISSLQSEDFAVYYCQ GP SVFPL AP S SKST S GGTAALGCLVKDYFPEPVTVSWN S GAL T
QYQNWPLTFGGGTKVEIKRTV SGVHTFPAVLQSSGLY SLSSVVTVP SSSLGTQTYICNVNHKP SN
AA AAPSVFIFPPSDEQLKSGTASVV TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLY
CLLNNFYPREAKVQWKVDNAL ITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCEE
QSGNSQESVTEQD SKD STY SL S QYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS
p
STLTLSKADYEKHKVYACEVT KAKGQPREPQVYTLPP SREEMTKNQVSLTCLVKGFYPSDIAVE
L.
HQGL SSPVTKSFNRGEC
WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV .
,
FSCSVMHEALHNHYTQKSLSLSPGK
..
(SEQ ID NO: 1288) (SEQ ID NO: 1289)
,
ATGGACATGAGGGTGCCCGCT ATGGACATGAGGGTGCCCGCTCAGCTCCTGGGGCTCCTGCT
.
,
,
CAGCTCCTGGGGCTCCTGCTG GCTGTGGCTGAGAGGTGCGCGCTGTCAGGTGCAGCTGGTGG
.
,
L.
,
CTGTGGCTGAGAGGTGCGCGC AGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGA
TGTGAAATCGTGATGACGCAG CTCTCCTGTGCAGCATCTGGATTCACCTTCAGTAACTATGGC
TCTCCAGCCACCCTGTCTGTG ATGCACTGGGTCCGCCAGGCTCCAGGCGAGGGGCTGGAGTG
TCTCCAGGGGAAAGAGCCAC GGTGGCAGCTATCTGGTTTGATGCAAGTGATAAATACTATG
c-1
oe CCTCTCCTGCAGGGCCAGTCA
CAGACGCCGTGAAGGGCCGATTCACCATCTCCAGAGACAAC
re)
01 NA GAGTGTTAGCAGCAACTTAGC
TCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGC
in CTGGTACCAGCAGAAACCTG
CGAGGACACGGCTGTGTATTACTGTGCGAGAGATATTGCGA
ci3
0.0 GCCAGGCTCCCAGGCTCCTCA
TTTTTGGAGTGGTCCCCGACTACTGGGGCCAGGGAACCCTG 00
-
n
TCTATGGTGCAGCCACCAGGG GTCACCGTGTCTAGTGCCTCCACCAAGGGCCCATCGGTCTTC
1-3
CCACTGGTATCCCAGCCAGGT CCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGC
cp
TCAGTGGCAGTGGGTCTGGGA GGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGG
n.)
o
CAGAGTTCACTCTCACCATCA TGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTG
oe
GCAGCCTGCAGTCTGAAGATT CACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCC
'a
TTGCAGTTTATTACTGTCAGC CTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCAC
oe
cA
oe
182
A-2164-WO-PCT
AGTATAATAACTGGCCTCTCA CCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACA
CTTTCGGCGGAGGGACCAAG CCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAA
GTGGAGATCAAACGAACGGT ACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGG
0
n.)
GGCTGCACCATCTGTCTTCAT GGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACA
o
CTTCCCGCCATCTGATGAGCA CCCTCTACATCACCCGGGAGCCTGAGGTCACATGCGTGGTG
oe
i-J
GTTGAAATCTGGAACTGCCTC GTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTG
c,.)
--.1
TGTTGTGTGCCTGCTGAATAA GTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAG
o
o
CTTCTATCCCAGAGAGGCCAA CCGTGCGAGGAGCAGTACGGCAGCACGTACCGTTGCGTCAG
--.1
AGTACAGTGGAAGGTGGATA CGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGG
ACGCCCTCCAATCGGGTAACT AGTACAAGTGCAAGGTGTCCAACAAAGCCCTCCCAGCCCCC
CCCAGGAGAGTGTCACAGAG ATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAG
CAGGACAGCAAGGACAGCAC AACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATG
CTACAGCCTCAGCAGCACCCT ACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTT
GACGCTGAGCAAAGCAGACT CTATCCCAGCGATATCGCCGTGGAGTGGGAGAGCAATGGGC
ACGAGAAACACAAAGTCTAC AGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGAC
GCCTGCGAAGTCACCCATCAG TCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGAC
P
GGCCTGAGCTCGCCCGTCACA AAGAGTAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGT
o
L.
AAGAGCTTCAACAGGGGAGA GATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCC
.
,
GTGT TCTCCCTGTCTCCGGGTAAA
'
(SEQ ID NO: 1363 (SEQ ID NO: 1364
,
EIVMTQ SP ATL SVSPGERATLS QVQLVE SGGGVVQPGRSLRL SCAASGFTFSNYGMHWVRQAP
L.
,
,
CRASQSVSSNLAWYQQKPGQA GEGLEWVAAIWFDASDKYYADAVKGRFTISRDNSKNTLYLQ
.
,
L.
PRLLIYGAATRATGIPARFSGSG MNSLRAEDTAVYYCARDIAIFGVVPDYWGQGTLVTVSSASTK
,
SGTEFTLTIS SLQSEDFAVYYCQ GP SVFPL AP S SKST S GGTAALGCLVKDYFPEPVTVSWN S GAL T
QYNNWPLTFGGGTKVEIKRTV SGVHTFPAVLQS SGLY SLS SVVTVP S S SLGTQTYICNVNHKP SN
AA AAPSVFIFPPSDEQLKSGTASVV TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLY
CLLNNFYPREAKVQWKVDNAL ITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCEE
QSGNSQESVTEQD SKD STY SL S QYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS
STLTLSKADYEKHKVYACEVT KAKGQPREPQVYTLPP SREEMTKNQVSLTCLVKGFYPSDIAVE
HQGL S SPVTKSFNRGEC WE SNGQPENNYKTTPPVLD SD GSFFLY
SKL TVDKSRWQQGNV 00
n
FSCSVMHEALHNHYTQKSLSLSPGK
1-3
(SEQ ID NO: 1299) (SEQ ID NO: 1300)
cp
o
ATGGACATGAGGGTGCCCGCT
ATGGACATGAGGGTGCCCGCTCAGCTCCTGGGGCTCCTGCT n.)
o
in r- CAGCTCCTGGGGCTCCTGCTG
GCTGTGGCTGAGAGGTGCGCGCTGTCAGGTGCAGCTGGTGG oe
ci3 ci NA
CTGTGGCTGAGAGGTGCGCGC AGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGA
'a
¨
TGTGAAATCGTGCTGACGCAG CTCTCCTGTGCAGCATCTGGATTCACCTTCAGTAACTATGGC
oe
cA
oe
183
A-2164-WO-PCT
TCTCCAGCCACCCTGTCTCTG ATGCACTGGGTCCGCCAGGCTCCAGGCGAGGGGCTGGAGTG
TCTCCAGGGGAAAGAGCCAC GGTGGCAGCTATCTGGTTTGATGCAAGTGATAAATACTATG
CCTCTCCTGCAGGGCCAGTCA CAGACGCCGTGAAGGGCCGATTCACCATCTCCAGAGACAAC
0
t..)
GAGTGTTAGCAGCAACTTAGC TCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGC
o
CTGGTACCAGCAGAAACCTG CGAGGACACGGCTGTGTATTACTGTGCGAGAGATCAGGCGA
oe
GCCAGGCTCCCAGGCTCCTCA TTTTTGGAGTGGTCCCCGATTACTGGGGCCAGGGAACCCTG
c,.)
--.1
TCTATGGTGCAGCCACCAGGG GTCACCGTGTCTAGTGCCTCCACCAAGGGCCCATCGGTCTTC
o
o
CCACTGGTATCCCAGACAGGT CCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGC
--.1
TCAGTGGCAGTGGGTCTGGGA GGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGG
CAGAGTTCACTCTCACCATCA TGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTG
GCAGGCTGGAGCCTGAAGATT CACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCC
TTGCAGTTTATTACTGTCAGC CTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCAC
AGTATAATAACTGGCCTCTCA CCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACA
CTTTCGGCGGAGGGACCAAG CCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAA
GTGGAGATCAAACGAACGGT ACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGG
GGCTGCACCATCTGTCTTCAT GGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACA
P
CTTCCCGCCATCTGATGAGCA CCCTCTACATCACCCGGGAGCCTGAGGTCACATGCGTGGTG
o
L.
GTTGAAATCTGGAACTGCCTC GTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTG
.
,
TGTTGTGTGCCTGCTGAATAA GTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAG
'
CTTCTATCCCAGAGAGGCCAA CCGTGCGAGGAGCAGTACGGCAGCACGTACCGTTGCGTCAG
" AGTACAGTGGAAGGTGGATA
CGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGG Lo':
,
ACGCCCTCCAATCGGGTAACT AGTACAAGTGCAAGGTGTCCAACAAAGCCCTCCCAGCCCCC
.
,
L.
CCCAGGAGAGTGTCACAGAG ATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAG
,
CAGGACAGCAAGGACAGCAC AACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATG
CTACAGCCTCAGCAGCACCCT ACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTT
GACGCTGAGCAAAGCAGACT CTATCCCAGCGATATCGCCGTGGAGTGGGAGAGCAATGGGC
ACGAGAAACACAAAGTCTAC AGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGAC
GCCTGCGAAGTCACCCATCAG TCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGAC
GGCCTGAGCTCGCCCGTCACA AAGAGTAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGT
AAGAGCTTCAACAGGGGAGA GATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCC
00
GTGT TCTCCCTGTCTCCGGGTAAA
n
1-3
(SEQ ID NO: 1365 (SEQ ID NO: 1366
cp
EIVLTQSPATLSLSPGERATLSC QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMHWVRQAP
t..)
o
AA
RASQSVSSNLAWYQQKPGQAP GEGLEWVAAIWFDASDKYYADAVKGRFTISRDNSKNTLYLQ
oe
RLLIYGAATRATGIPDRFSGSGS MNSLRAEDTAVYYCARDQAIFGVVPDYWGQGTLVTVSSASTK
GTEFTLTISRLEPEDFAVYYCQ GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALT
oe
cA
oe
184
A-2164-WO-PCT
QYNNWPLTFGGGTKVEIKRTV SGVHTFPAVLQSSGLY SLSSVVTVP SSSLGTQTYICNVNHKP SN
AAPSVFIFPPSDEQLKSGTASVV TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLY
CLLNNFYPREAKVQWKVDNAL ITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCEE
0
n.)
QSGNSQESVTEQD SKD STY SL S QYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS
o
STLTLSKADYEKHKVYACEVT KAKGQPREPQVYTLPP SREEMTKNQVSLTCLVKGFYPSDIAVE
oe
i-J
HQGL SSPVTKSFNRGEC WE SNGQPENNYKTTPPVLD SD GSFFLY
SKL TVDKSRWQQGNV c,.)
--.1
F SC SVMHEALHNHYTQKSL SL SP GK
o
o
(SEQ ID NO: 1309) (SEQ ID NO: 1310)
--.1
ATGGACATGAGGGTGCCCGCT ATGGACATGAGGGTGCCCGCTCAGCTCCTGGGGCTCCTGCT
CAGCTCCTGGGGCTCCTGCTG GCTGTGGCTGAGAGGTGCGCGCTGTCAGGTGCAGCTGGTGG
CTGTGGCTGAGAGGTGCGCGC AGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGA
TGTGAAATCGTGCTGACGCAG CTCTCCTGTGCAGCATCTGGATTCACCTTCAGTAACTATGGC
TCTCCAGCCACCCTGTCTCTG ATGCACTGGGTCCGCCAGGCTCCAGGCGAGGGGCTGGAGTG
TCTCCAGGGGAAAGAGCCAC GGTGGCAGCTATCTGGTTTGATGCAAGTGATAAATACTATG
CCTCTCCTGCAGGGCCAGTCA CAGACGCCGTGAAGGGCCGATTCACCATCTCCAGAGACAAC
GAGTGTTAGCGAACACTTAGC TCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGC
p
CTGGTACCAGCAGAAACCTG CGAGGACACGGCTGTGTATTACTGTGCGAGAGATCTGGCGA
L.
GCCAGGCTCCCAGGCTCCTCA TTTTTGGAGTGATTCCCGACTACTGGGGCCAGGGAACCCTG
.
,
TCTACGAAGCAGCCACCAGG GTCACCGTGTCTAGTGCCTCCACCAAGGGCCCATCGGTCTTC
..
GCCACTGGTATCCCAGACAGG CCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGC
o ,
o
TTCAGTGGCAGTGGGTCTGGG
GGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGG L.
,
re)
r
01 NA ACAGAGTTCACTCTCACCATC
TGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTG
.
,
L.
in AGCAGGCTGGAGCCTGAAGA
CACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCC
,
ci3
0.0 TTTTGCAGTTTATTACTGTCAG
CTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCAC
¨
CAGTATCAGAACTGGCCTCTC CCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACA
ACTTTCGGCGGAGGGACCAA CCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAA
GGTGGAGATCAAACGAACGG ACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGG
TGGCTGCACCATCTGTCTTCA GGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACA
TCTTCCCGCCATCTGATGAGC CCCTCTACATCACCCGGGAGCCTGAGGTCACATGCGTGGTG
AGTTGAAATCTGGAACTGCCT GTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTG
00
CTGTTGTGTGCCTGCTGAATA GTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAG
n
1-3
ACTTCTATCCCAGAGAGGCCA CCGTGCGAGGAGCAGTACGGCAGCACGTACCGTTGCGTCAG
cp
AAGTACAGTGGAAGGTGGAT CGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGG
n.)
o
AACGCCCTCCAATCGGGTAAC AGTACAAGTGCAAGGTGTCCAACAAAGCCCTCCCAGCCCCC
oe
TCCCAGGAGAGTGTCACAGA ATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAG
'a
GCAGGACAGCAAGGACAGCA AACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATG
oe
cA
oe
185
A-2164-WO-PCT
CCTACAGCCTCAGCAGCACCC ACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTT
TGACGCTGAGCAAAGCAGAC CTATCCCAGCGATATCGCCGTGGAGTGGGAGAGCAATGGGC
TACGAGAAACACAAAGTCTA AGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGAC
0
n.)
CGCCTGCGAAGTCACCCATCA TCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGAC
=
GGGCCTGAGCTCGCCCGTCAC AAGAGTAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGT
oe
i-J
AAAGAGCTTCAACAGGGGAG GATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCC
c,.)
--.1
AGTGT TCTCCCTGTCTCCGGGTAAA
o
o
(SEQ ID NO: 1367 (SEQ ID NO: 1368
--.1
EIVLTQ SPATLSL SP GERATL SC QVQLVE SGGGVVQPGRSLRL SCAASGFTFSNYGMHWVRQAP
RASQSVSEHLAWYQQKPGQAP GEGLEWVAAIWFDASDKYYADAVKGRFTISRDNSKNTLYLQ
RLLIYEAATRATGIPD RF S GS GS MN SLRAEDTAVYYCARDLAIFGVIPDYWGQGTLVTVS SASTK
GTEFTLTISRLEPEDFAVYYCQ GP SVFPL AP S SKST S GGTAALGCLVKDYFPEPVTVSWN S GAL T
QYQNWPLTFGGGTKVEIKRTV SGVHTFPAVLQS SGLY SLS SVVTVP S S SLGTQTYICNVNHKP SN
AA AAPSVFIFPPSDEQLKSGTASVV TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLY
CLLNNFYPREAKVQWKVDNAL ITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCEE
QSGNSQESVTEQD SKD STY SL S QYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS
p
STLTLSKADYEKHKVYACEVT KAKGQPREPQVYTLPP SREEMTKNQVSLTCLVKGFYPSDIAVE
L.
HQGL S SPVTKSFNRGEC WE SNGQPENNYKTTPPVLD SD GSFFLY
SKL TVDKSRWQQGNV .
,
FSCSVMHEALHNHYTQKSLSLSPGK
..
(SEQ ID NO: 1319) (SEQ ID NO: 1320)
,
L.
,
,
.
,
L.
,
00
n
,-i
cp
w
=
oe
'a
oe
cA
oe
186
A-2164-WO-PCT
ATGGACATGAGGGTGCCCGCT ATGGACATGAGGGTGCCCGCTCAGCTCCTGGGGCTCCTGCT
CAGCTCCTGGGGCTCCTGCTG GCTGTGGCTGAGAGGTGCGCGCTGTCAGGTGCAGCTGGTGG
CTGTGGCTGAGAGGTGCGCGC AGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGA
0
t..)
TGTGAAATCGTGCTGACGCAG CTCTCCTGTGCAGCATCTGGATTCACCTTCAGTAACTATGGC
o
TCTCCAGCCACCCTGTCTCTG ATGCACTGGGTCCGCCAGGCTCCAGGCGAGGGGCTGGAGTG
oe
TCTCCAGGGGAAAGAGCCAC GGTGGCAGCTATCTGGTTTGATGCAAGTGATAAATACTATG
c,.)
--.1
CCTCTCCTGCAGGGCCAGTCA CAGACGCCGTGAAGGGCCGATTCACCATCTCCAGAGACAAC
o
GAGTGTTAGCAGCAACTTAGC TCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGC
--.1
CTGGTACCAGCAGAAACCTG CGAGGACACGGCTGTGTATTACTGTGCGAGAGATATTGCGA
GCCAGGCTCCCAGGCTCCTCA TTTTTGGAGTGGTCCCCGACTACTGGGGCCAGGGAACCCTG
TCTATGGTGCAGCCACCAGGG GTCACCGTGTCTAGTGCCTCCACCAAGGGCCCATCGGTCTTC
CCACTGGTATCCCAGACAGGT CCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGC
TCAGTGGCAGTGGGTCTGGGA GGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGG
CAGAGTTCACTCTCACCATCA TGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTG
GCAGGCTGGAGCCTGAAGATT CACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCC
TTGCAGTTTATTACTGTCAGC CTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCAC
P
o
o
AGTATAATAACTGGCCTCTCA
CCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACA o
7r
L.
NA CTTTCGGCGGAGGGACCAAG CCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAA
.
,
in GTGGAGATCAAACGAACGGT
ACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGG '
ci3
.
0.0 GGCTGCACCATCTGTCTTCAT
GGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACA " --
CTTCCCGCCATCTGATGAGCA CCCTCTACATCACCCGGGAGCCTGAGGTCACATGCGTGGTG
Lo':
,
GTTGAAATCTGGAACTGCCTC GTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTG
.
,
L.
TGTTGTGTGCCTGCTGAATAA GTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAG
,
CTTCTATCCCAGAGAGGCCAA CCGTGCGAGGAGCAGTACGGCAGCACGTACCGTTGCGTCAG
AGTACAGTGGAAGGTGGATA CGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGG
ACGCCCTCCAATCGGGTAACT AGTACAAGTGCAAGGTGTCCAACAAAGCCCTCCCAGCCCCC
CCCAGGAGAGTGTCACAGAG ATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAG
CAGGACAGCAAGGACAGCAC AACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATG
CTACAGCCTCAGCAGCACCCT ACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTT
GACGCTGAGCAAAGCAGACT CTATCCCAGCGATATCGCCGTGGAGTGGGAGAGCAATGGGC
00
ACGAGAAACACAAAGTCTAC AGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGAC
n
,-i
GCCTGCGAAGTCACCCATCAG TCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGAC
GGCCTGAGCTCGCCCGTCACA AAGAGTAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGT
ci)
r.)
o
AAGAGCTTCAACAGGGGAGA GATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCC
oe
GTGT TCTCCCTGTCTCCGGGTAAA
(SEQ ID NO: 1369 (SEQ ID NO: 1370
oe
cA
oe
187
A-2164-W0- P CT
EIVLTQ SPATLSL SP GERATL SC QVQLVE SGGGVVQPGRSLRL SCAASGFTFSNYGMHWVRQAP
RASQSVSSNLAWYQQKPGQAP GEGLEWVAAIWFDASDKYYADAVKGRFTISRDNSKNTLYLQ
RLLIYGAATRATGIPDRFSGSGS MNSLRAEDTAVYYCARDIAIFGVVPDYWGQGTLVTVSSASTK
0
n.)
GTEFTLTISRLEPEDFAVYYCQ GP SVFPL AP S SKST S GGTAALGCLVKDYFPEPVTVSWN S GAL T
o
QYNNWPLTFGGGTKVEIKRTV SGVHTFPAVLQSSGLY SLSSVVTVP SSSLGTQTYICNVNHKP SN
oe
i-J
AA AAPSVFIFPPSDEQLKSGTASVV TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLY
c,.)
--.1
CLLNNFYPREAKVQWKVDNAL ITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCEE
o
o
QSGNSQESVTEQD SKD STY SL S QYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS
--.1
STLTLSKADYEKHKVYACEVT KAKGQPREPQVYTLPP SREEMTKNQVSLTCLVKGFYPSDIAVE
HQGL SSPVTKSFNRGEC WE SNGQPENNYKTTPPVLD SD GSFFLY
SKL TVDKSRWQQGNV
FSCSVMHEALHNHYTQKSLSLSPGK
(SEQ ID NO: 1329) (SEQ ID NO: 1230)
ATGGACATGAGGGTGCCCGCT ATGGACATGAGGGTGCCCGCTCAGCTCCTGGGGCTCCTGCT
CAGCTCCTGGGGCTCCTGCTG GCTGTGGCTGAGAGGTGCGCGCTGTCAGGTGCAGCTGGTGG
CTGTGGCTGAGAGGTGCGCGC AGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGA
TGTGAAATCGTGCTGACGCAG CTCTCCTGTGCAGCATCTGGATTCACCTTCAGTAACTATGGC
p
TCTCCAGCCACCCTGTCTCTG ATGCACTGGGTCCGCCAGGCTCCAGGCGAGGGGCTGGAGTG
L.
TCTCCAGGGGAAAGAGCCAC GGTGGCAGCTATCTGGTTTGATGCAAGTGATAAATACTATG
.
,
CCTCTCCTGCAGGGCCAGTCA CAGACGCCGTGAAGGGCCGATTCACCATCTCCAGAGACAAC
..
GAGTGTTGATCTGCACTTAGC TCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGC
,
CTGGTACCAGCAGAAACCTG CGAGGACACGGCTGTGTATTACTGTGCGAGAGATTTGGCGA
L.
,
,
GCCAGGCTCCCAGGCTCCTCA TTTTTGGAGTGGTCCCCGACTACTGGGGCCAGGGAACCCTG
.
,
o
TCTACGAAGCAGCCACCAGG
GTCACCGTGTCTAGTGCCTCCACCAAGGGCCCATCGGTCTTC ,
.7r
re)
01 GCCACTGGTATCCCAGACAGG
CCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGC
NA
in TTCAGTGGCAGTGGGTCTGGG
GGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGG
ci3 ACAGAGTTCACTCTCACCATC
TGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTG
0.0
¨
AGCAGGCTGGAGCCTGAAGA CACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCC
TTTTGCAGTTTATTACTGTCAG CTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCAC
CAGTATCAGAACTGGCCTCTC CCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACA
ACTTTCGGCGGAGGGACCAA CCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAA
00
GGTGGAGATCAAACGAACGG ACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGG
n
1-3
TGGCTGCACCATCTGTCTTCA GGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACA
cp
TCTTCCCGCCATCTGATGAGC CCCTCTACATCACCCGGGAGCCTGAGGTCACATGCGTGGTG
n.)
o
AGTTGAAATCTGGAACTGCCT GTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTG
oe
CTGTTGTGTGCCTGCTGAATA GTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAG
'a
ACTTCTATCCCAGAGAGGCCA CCGTGCGAGGAGCAGTACGGCAGCACGTACCGTTGCGTCAG
oe
cA
oe
188
A-2164-WO-PCT
AAGTACAGTGGAAGGTGGAT CGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGG
AACGCCCTCCAATCGGGTAAC AGTACAAGTGCAAGGTGTCCAACAAAGCCCTCCCAGCCCCC
TCCCAGGAGAGTGTCACAGA ATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAG
0
n.)
GCAGGACAGCAAGGACAGCA AACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATG
o
CCTACAGCCTCAGCAGCACCC ACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTT
oe
i-J
TGACGCTGAGCAAAGCAGAC CTATCCCAGCGATATCGCCGTGGAGTGGGAGAGCAATGGGC
c,.)
--.1
TACGAGAAACACAAAGTCTA AGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGAC
o
o
CGCCTGCGAAGTCACCCATCA TCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGAC
--.1
GGGCCTGAGCTCGCCCGTCAC AAGAGTAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGT
AAAGAGCTTCAACAGGGGAG GATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCC
AGTGT TCTCCCTGTCTCCGGGTAAA
(SEQ ID NO: 1371 (SEQ ID NO: 1372
EIVLTQ SPATLSL SP GERATL SC QVQLVE SGGGVVQPGRSLRL SCAASGFTFSNYGMHWVRQAP
RASQSVDLHLAWYQQKPGQAP GEGLEWVAAIWFDASDKYYADAVKGRFTISRDNSKNTLYLQ
RLLIYEAATRATGIPDRFSGSGS MNSLRAEDTAVYYCARDLAIFGVVPDYWGQGTLVTVSSASTK
GTEFTLTISRLEPEDFAVYYCQ GP SVFPL AP S SKST S GGTAALGCLVKDYFPEPVTVSWN S GAL T
p
QYQNWPLTFGGGTKVEIKRTV SGVHTFPAVLQS SGLY SLS SVVTVP S S SLGTQTYICNVNHKP SN
L.
AA AAPSVFIFPPSDEQLKSGTASVV TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLY
.
,
CLLNNFYPREAKVQWKVDNAL ITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCEE
..
QSGNSQESVTEQD SKD STY SL S QYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS
,
STLTLSKADYEKHKVYACEVT KAKGQPREPQVYTLPP SREEMTKNQVSLTCLVKGFYPSDIAVE
.
,
,
HQGL S SPVTKSFNRGEC WE SNGQPENNYKTTPPVLD SD GSFFLY
SKL TVDKSRWQQGNV .
,
L.
FSCSVMHEALHNHYTQKSLSLSPGK
,
(SEQ ID NO: 1339) (SEQ ID NO: 1340)
ATGGACATGAGGGTGCCCGCT ATGGACATGAGGGTGCCCGCTCAGCTCCTGGGGCTCCTGCT
CAGCTCCTGGGGCTCCTGCTG GCTGTGGCTGAGAGGTGCGCGCTGTCAGGTGCAGCTGGTGG
CTGTGGCTGAGAGGTGCGCGC AGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGA
TGTGAAATCGTGCTGACGCAG CTCTCCTGTGCAGCATCTGGATTCACCTTCAGTAACTATGGC
.7r
o TCTCCAGCCACCCTGTCTCTG ATGCACTGGGTCCGCCAGGCTCCAGGCGAGGGGCTGGAGTG
.7r
o
TCTCCAGGGGAAAGAGCCAC
GGTGGCAGCTATCTGGTTTGATGCAAGTGATAAATACTATG 00
NA
n
in CCTCTCCTGCAGGGCCAGTCA
CAGACGCCGTGAAGGGCCGATTCACCATCTCCAGAGACAAC 1-3
ci3
0.0 GAGTGTTAACCTGAACTTAGC
TCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGC
¨
cp
CTGGTACCAGCAGAAACCTG CGAGGACACGGCTGTGTATTACTGTGCGAGAGATTTGGCGA
n.)
o
GCCAGGCTCCCAGGCTCCTCA TTTTTGGAGTGGTCCCCGACTACTGGGGCCAGGGAACCCTG
oe
TCTACCAGGCAGCCACCAGG GTCACCGTGTCTAGTGCCTCCACCAAGGGCCCATCGGTCTTC
'a
GCCACTGGTATCCCAGACAGG CCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGC
oe
cA
oe
189
A-2164-WO-PCT
TTCAGTGGCAGTGGGTCTGGG GGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGG
ACAGAGTTCACTCTCACCATC TGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTG
AGCAGGCTGGAGCCTGAAGA CACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCC
0
n.)
TTTTGCAGTTTATTACTGTCAG CTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCAC
=
CAGTATAACCAGTGGCCTCTC CCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACA
oe
i-J
ACTTTCGGCGGAGGGACCAA CCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAA
c,.)
--.1
GGTGGAGATCAAACGAACGG ACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGG
o
o
TGGCTGCACCATCTGTCTTCA GGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACA
--.1
TCTTCCCGCCATCTGATGAGC CCCTCTACATCACCCGGGAGCCTGAGGTCACATGCGTGGTG
AGTTGAAATCTGGAACTGCCT GTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTG
CTGTTGTGTGCCTGCTGAATA GTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAG
ACTTCTATCCCAGAGAGGCCA CCGTGCGAGGAGCAGTACGGCAGCACGTACCGTTGCGTCAG
AAGTACAGTGGAAGGTGGAT CGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGG
AACGCCCTCCAATCGGGTAAC AGTACAAGTGCAAGGTGTCCAACAAAGCCCTCCCAGCCCCC
TCCCAGGAGAGTGTCACAGA ATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAG
GCAGGACAGCAAGGACAGCA AACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATG
P
CCTACAGCCTCAGCAGCACCC ACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTT
o
L.
TGACGCTGAGCAAAGCAGAC CTATCCCAGCGATATCGCCGTGGAGTGGGAGAGCAATGGGC
.
,
TACGAGAAACACAAAGTCTA AGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGAC
'
CGCCTGCGAAGTCACCCATCA TCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGAC
" GGGCCTGAGCTCGCCCGTCAC
AAGAGTAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGT Lo':
,
AAAGAGCTTCAACAGGGGAG GATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCC
.
,
L.
AGTGT TCTCCCTGTCTCCGGGTAAA
,
(SEQ ID NO: 1373 (SEQ ID NO: 1374
EIVLTQSPATLSLSPGERATLSC QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMHWVRQAP
RASQSVNLNLAWYQQKPGQAP GEGLEWVAAIWFDASDKYYADAVKGRFTISRDNSKNTLYLQ
RLLIYQAATRATGIPDRFSGSGS MNSLRAEDTAVYYCARDLAIFGVVPDYWGQGTLVTVSSASTK
GTEFTLTISRLEPEDFAVYYCQ GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALT
QYNQWPLTFGGGTKVEIKRTV SGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN
AA AAPSVFIFPPSDEQLKSGTASVV TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLY
00
n
CLLNNFYPREAKVQWKVDNAL ITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCEE
1-3
QSGNSQESVTEQDSKDSTYSLS QYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS
cp
STLTLSKADYEKHKVYACEVT KAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE
n.)
o
HQGLSSPVTKSFNRGEC
WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV
oe
FSCSVMHEALHNHYTQKSLSLSPGK
'a
(SEQ ID NO: 1349) (SEQ ID NO: 1350)
oe
cA
oe
190
A-2164-WO-PCT
ATGGACATGAGGGTGCCCGCT ATGGACATGAGGGTGCCCGCTCAGCTCCTGGGGCTCCTGCT
CAGCTCCTGGGGCTCCTGCTG GCTGTGGCTGAGAGGTGCGCGCTGTCAGGTGCAGCTGGTGG
CTGTGGCTGAGAGGTGCGCGC AGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGA
0
t..)
TGTGAAATCGTGCTGACGCAG CTCTCCTGTGCAGCATCTGGATTCACCTTCCAGAACTATGGC
o
TCTCCAGCCACCCTGTCTCTG ATGCACTGGGTCCGCCAGGCTCCAGGCGAGGGGCTGGAGTG
oe
TCTCCAGGGGAAAGAGCCAC GGTGGCAGCTATCTGGTTTGATGCGTCTGACAAATACTATG
c,.)
--.1
CCTCTCCTGCAGGGCCAGTCA CAGACGCCGTGAAGGGCCGATTCACCATCTCCAGAGACAAC
o
GAGTGTTTTCAGCCACTTAGC TCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGC
--.1
CTGGTACCAGCAGAAACCTG CGAGGACACGGCTGTGTATTACTGTGCGAGAGATCTTGCGA
GCCAGGCTCCCAGGCTCCTCA TTTTTGGAGTGGTCCCCGACTACTGGGGCCAGGGAACCCTG
TCTACGAAGCAGCCACCAGG GTCACCGTGTCTAGTGCCTCCACCAAGGGCCCATCGGTCTTC
GCCACTGGTATCCCAGACAGG CCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGC
TTCAGTGGCAGTGGGTCTGGG GGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGG
ACAGAGTTCACTCTCACCATC TGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTG
AGCAGGCTGGAGCCTGAAGA CACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCC
TTTTGCAGTTTATTACTGTCAG CTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCAC
P
in
o
CAGTATCAGAACTGGCCTCTC
CCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACA o
7r
L.
NA ACTTTCGGCGGAGGGACCAA CCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAA
.
,
in GGTGGAGATCAAACGAACGG
ACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGG '
ci3
.
0.0 TGGCTGCACCATCTGTCTTCA
GGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACA " --
TCTTCCCGCCATCTGATGAGC CCCTCTACATCACCCGGGAGCCTGAGGTCACATGCGTGGTG
y
,
AGTTGAAATCTGGAACTGCCT GTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTG
.
,
L.
CTGTTGTGTGCCTGCTGAATA GTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAG
,
ACTTCTATCCCAGAGAGGCCA CCGTGCGAGGAGCAGTACGGCAGCACGTACCGTTGCGTCAG
AAGTACAGTGGAAGGTGGAT CGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGG
AACGCCCTCCAATCGGGTAAC AGTACAAGTGCAAGGTGTCCAACAAAGCCCTCCCAGCCCCC
TCCCAGGAGAGTGTCACAGA ATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAG
GCAGGACAGCAAGGACAGCA AACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATG
CCTACAGCCTCAGCAGCACCC ACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTT
TGACGCTGAGCAAAGCAGAC CTATCCCAGCGATATCGCCGTGGAGTGGGAGAGCAATGGGC
00
TACGAGAAACACAAAGTCTA AGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGAC
n
,-i
CGCCTGCGAAGTCACCCATCA TCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGAC
GGGCCTGAGCTCGCCCGTCAC AAGAGTAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGT
cp
n.)
o
AAAGAGCTTCAACAGGGGAG GATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCC
oe
AGTGT TCTCCCTGTCTCCGGGTAAA
(SEQ ID NO: 1375 (SEQ ID NO: 1376
oe
cA
oe
191
A-2164-W0- P CT
EIVLTQ SPATLSL SP GERATL SC QVQLVE SGGGVVQPGRSLRL SCAASGFTFQNYGMHWVRQAP
RASQSVFSHLAWYQQKPGQAP GEGLEWVAAIWFDASDKYYADAVKGRFTISRDNSKNTLYLQ
RLLIYEAATRATGIPDRFSGSGS MNSLRAEDTAVYYCARDLAIFGVVPDYWGQGTLVTVSSASTK
0
n.)
GTEFTLTISRLEPEDFAVYYCQ GP SVFPL AP S SKST S GGTAALGCLVKDYFPEPVTVSWN S GAL T
=
QYQNWPLTFGGGTKVEIKRTV SGVHTFPAVLQS SGLY SLS SVVTVP S S SLGTQTYICNVNHKP SN
oe
i-J
AA AAPSVFIFPPSDEQLKSGTASVV TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLY
c,.)
--.1
CLLNNFYPREAKVQWKVDNAL ITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCEE
o
o
QSGNSQESVTEQD SKD STY SL S QYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS
--.1
STLTLSKADYEKHKVYACEVT KAKGQPREPQVYTLPP SREEMTKNQVSLTCLVKGFYPSDIAVE
HQGL S SPVTKSFNRGEC WE SNGQPENNYKTTPPVLD SD GSFFLY
SKL TVDKSRWQQGNV
FSCSVMHEALHNHYTQKSLSLSPGK
(SEQ ID NO: 1359) (SEQ ID NO: 1360)
P
.
L.
.
,,
,
L.
,,
.
,
L.
,
,
.
,
L.
,
00
n
,-i
cp
t..,
=
oe
'a
oe
cA
oe
192
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[0203] In one embodiment the antibody or fragment thereof comprises a light
chain variable
region comprising a sequence selected from the group consisting of SEQ ID NOs:
723, 727,
731, 735, 739, 743, 747, 751, 755, 759, 763, 767, 771, 775, 779, 783, 787,
791, 795, 799,
803, 807, 811, 815, 819, 823, 827, 831, 835, 839, 843, 847, 851, 855, 859,
863, 867, 871,
875, 879, 883, 887, 891, 895, 899, 903, 907, 911, 915, 919, 923, 927, 931,
935, 939, 943,
947, 951, 955, 959, 1286, 1296, 1306, 1316, 1326, 1336, 1346, and 1356. In one
embodiment
the antibody or fragment thereof comprises a heavy chain variable region
comprising a
sequence selected from the group consisting of SEQ ID NOs: 724, 728, 732, 736,
740, 744,
748, 752, 756, 760, 764, 768, 772, 776, 780, 784, 788, 792, 796, 800, 804,
808, 812, 816,
820, 824, 828, 832, 836, 840, 844, 848, 852, 856, 860, 864, 868, 872, 876,
880, 884, 888,
892, 896, 900, 904, 908, 912, 916, 920, 924, 928, 932, 936, 940, 944, 948,
952, 956, 960,
1287, 1297, 1307, 1317, 1327, 1337, 1347, and 1357. In one embodiment the
antibody or
fragment thereof comprises a light chain variable region comprising a sequence
selected from
the group consisting of SEQ ID NOs: 723, 727, 731, 735, 739, 743, 747, 751,
755, 759, 763,
767,771,775,779,783,787,791,795,799,803,807,811,815,819,823,827,831,835,
839,843,847,851,855,859,863,867,871,875,879,883,887,891,895,899,903,907,
911,915,919,923,927,931,935,939,943,947,951,955,959,1286,1296,1306,1316,
1326, 1336, 1346, and 1356 and a heavy chain variable region comprising a
sequence
selected from the group consisting of SEQ ID NOs: 724, 728, 732, 736, 740,
744, 748, 752,
756, 760, 764, 768, 772, 776, 780, 784, 788, 792, 796, 800, 804, 808, 812,
816, 820, 824,
828, 832, 836, 840, 844, 848, 852, 856, 860, 864, 868, 872, 876, 880, 884,
888, 892, 896,
900, 904, 908, 912, 916, 920, 924, 928, 932, 936, 940, 944, 948, 952, 956,
960, 1287, 1297,
1307, 1317, 1327, 1337, 1347, and 1357.
[0204] In one embodiment the antibody or fragment thereof comprises a
combination of light
chain variable region and a heavy chain variable region selected from the
group consisting of
a light chain variable region comprising SEQ ID NO: 723 and a heavy chain
variable region
comprising SEQ ID NO: 724; a light chain variable region comprising SEQ ID NO:
727 and
a heavy chain variable region comprising SEQ ID NO: 728; a light chain
variable region
comprising SEQ ID NO: 731 and a heavy chain variable region comprising SEQ ID
NO: 732;
a light chain variable region comprising SEQ ID NO: 735 and a heavy chain
variable region
comprising SEQ ID NO: 736; a light chain variable region comprising SEQ ID NO:
739 and
a heavy chain variable region comprising SEQ ID NO: 740; a light chain
variable region
comprising SEQ ID NO: 743 and a heavy chain variable region comprising SEQ ID
NO: 744;
a light chain variable region comprising SEQ ID NO: 747 and a heavy chain
variable region
193
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comprising SEQ ID NO: 748; a light chain variable region comprising SEQ ID NO:
751 and
a heavy chain variable region comprising SEQ ID NO: 752; a light chain
variable region
comprising SEQ ID NO: 755 and a heavy chain variable region comprising SEQ ID
NO: 756;
a light chain variable region comprising SEQ ID NO: 759 and a heavy chain
variable region
comprising SEQ ID NO: 760; a light chain variable region comprising SEQ ID NO:
763 and
a heavy chain variable region comprising SEQ ID NO: 764; a light chain
variable region
comprising SEQ ID NO: 767 and a heavy chain variable region comprising SEQ ID
NO: 768;
a light chain variable region comprising SEQ ID NO: 771 and a heavy chain
variable region
comprising SEQ ID NO: 772; a light chain variable region comprising SEQ ID NO:
775 and
a heavy chain variable region comprising SEQ ID NO: 776; a light chain
variable region
comprising SEQ ID NO: 779 and a heavy chain variable region comprising SEQ ID
NO: 780;
a light chain variable region comprising SEQ ID NO: 783 and a heavy chain
variable region
comprising SEQ ID NO: 784; a light chain variable region comprising SEQ ID NO:
787 and
a heavy chain variable region comprising SEQ ID NO: 788; a light chain
variable region
comprising SEQ ID NO: 791 and a heavy chain variable region comprising SEQ ID
NO: 792;
a light chain variable region comprising SEQ ID NO: 795 and a heavy chain
variable region
comprising SEQ ID NO: 796; a light chain variable region comprising SEQ ID NO:
799 and
a heavy chain variable region comprising SEQ ID NO: 800; a light chain
variable region
comprising SEQ ID NO: 803 and a heavy chain variable region comprising SEQ ID
NO: 804;
a light chain variable region comprising SEQ ID NO: 807 and a heavy chain
variable region
comprising SEQ ID NO: 808; a light chain variable region comprising SEQ ID NO:
811 and
a heavy chain variable region comprising SEQ ID NO: 812; a light chain
variable region
comprising SEQ ID NO: 815 and a heavy chain variable region comprising SEQ ID
NO: 816;
a light chain variable region comprising SEQ ID NO: 819 and a heavy chain
variable region
comprising SEQ ID NO: 820; a light chain variable region comprising SEQ ID NO:
823 and
a heavy chain variable region comprising SEQ ID NO: 824; a light chain
variable region
comprising SEQ ID NO: 827 and a heavy chain variable region comprising SEQ ID
NO: 828;
a light chain variable region comprising SEQ ID NO: 831 and a heavy chain
variable region
comprising SEQ ID NO: 832; a light chain variable region comprising SEQ ID NO:
835 and
a heavy chain variable region comprising SEQ ID NO: 836; a light chain
variable region
comprising SEQ ID NO: 839 and a heavy chain variable region comprising SEQ ID
NO: 840;
a light chain variable region comprising SEQ ID NO: 843 and a heavy chain
variable region
comprising SEQ ID NO: 844; a light chain variable region comprising SEQ ID NO:
847 and
a heavy chain variable region comprising SEQ ID NO: 848; a light chain
variable region
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comprising SEQ ID NO: 851 and a heavy chain variable region comprising SEQ ID
NO: 852;
a light chain variable region comprising SEQ ID NO: 855 and a heavy chain
variable region
comprising SEQ ID NO: 856; a light chain variable region comprising SEQ ID NO:
859 and
a heavy chain variable region comprising SEQ ID NO: 860; a light chain
variable region
comprising SEQ ID NO: 863 and a heavy chain variable region comprising SEQ ID
NO: 864;
a light chain variable region comprising SEQ ID NO: 867 and a heavy chain
variable region
comprising SEQ ID NO: 868; a light chain variable region comprising SEQ ID NO:
871 and
a heavy chain variable region comprising SEQ ID NO: 872; a light chain
variable region
comprising SEQ ID NO: 875 and a heavy chain variable region comprising SEQ ID
NO: 876;
a light chain variable region comprising SEQ ID NO: 879 and a heavy chain
variable region
comprising SEQ ID NO: 880; a light chain variable region comprising SEQ ID NO:
883 and
a heavy chain variable region comprising SEQ ID NO: 884; a light chain
variable region
comprising SEQ ID NO: 887 and a heavy chain variable region comprising SEQ ID
NO: 888;
a light chain variable region comprising SEQ ID NO: 891 and a heavy chain
variable region
comprising SEQ ID NO: 892; a light chain variable region comprising SEQ ID NO:
895 and
a heavy chain variable region comprising SEQ ID NO: 896; a light chain
variable region
comprising SEQ ID NO: 899 and a heavy chain variable region comprising SEQ ID
NO: 900;
a light chain variable region comprising SEQ ID NO: 903 and a heavy chain
variable region
comprising SEQ ID NO: 904; a light chain variable region comprising SEQ ID NO:
907 and
a heavy chain variable region comprising SEQ ID NO: 908; a light chain
variable region
comprising SEQ ID NO: 911 and a heavy chain variable region comprising SEQ ID
NO: 912;
a light chain variable region comprising SEQ ID NO: 915 and a heavy chain
variable region
comprising SEQ ID NO: 916; a light chain variable region comprising SEQ ID NO:
919 and
a heavy chain variable region comprising SEQ ID NO: 920; a light chain
variable region
comprising SEQ ID NO: 923 and a heavy chain variable region comprising SEQ ID
NO: 924;
a light chain variable region comprising SEQ ID NO: 927 and a heavy chain
variable region
comprising SEQ ID NO: 928; a light chain variable region comprising SEQ ID NO:
931 and
a heavy chain variable region comprising SEQ ID NO: 932; a light chain
variable region
comprising SEQ ID NO: 935 and a heavy chain variable region comprising SEQ ID
NO: 936;
a light chain variable region comprising SEQ ID NO: 939 and a heavy chain
variable region
comprising SEQ ID NO: 940; a light chain variable region comprising SEQ ID NO:
943 and
a heavy chain variable region comprising SEQ ID NO: 944; a light chain
variable region
comprising SEQ ID NO: 947 and a heavy chain variable region comprising SEQ ID
NO: 948;
a light chain variable region comprising SEQ ID NO: 951 and a heavy chain
variable region
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comprising SEQ ID NO: 952; a light chain variable region comprising SEQ ID NO:
955 and
a heavy chain variable region comprising SEQ ID NO: 956; a light chain
variable region
comprising SEQ ID NO: 959 and a heavy chain variable region comprising SEQ ID
NO: 960;
a light chain variable region comprising SEQ ID NO: 1286 and a heavy chain
variable region
comprising SEQ ID NO: 1287; a light chain variable region comprising SEQ ID
NO: 1296
and a heavy chain variable region comprising SEQ ID NO: 1297; a light chain
variable
region comprising SEQ ID NO: 1306 and a heavy chain variable region comprising
SEQ ID
NO: 1307; a light chain variable region comprising SEQ ID NO: 1316 and a heavy
chain
variable region comprising SEQ ID NO: 1317; alight chain variable region
comprising SEQ
ID NO: 1326 and a heavy chain variable region comprising SEQ ID NO: 1327; a
light chain
variable region comprising SEQ ID NO: 1336 and a heavy chain variable region
comprising
SEQ ID NO: 1337; alight chain variable region comprising SEQ ID NO: 1346 and a
heavy
chain variable region comprising SEQ ID NO: 1347; and a light chain variable
region
comprising SEQ ID NO: 1356 and a heavy chain variable region comprising SEQ ID
NO:
1357.
[0205] In one embodiment the antibody or fragment thereof comprises a light
chain variable
region encoded by a polynucleotide sequence selected from the group consisting
of SEQ ID
1`0Ds:721,725,729,733,737,741,745,749,753,757,761,765,769,773,777,781,785,
789,793,797,801,805,809,813,817,821,825,829,833,837,841,845,849,853,857,
861,865,869,873,877,881,885,889,893,897,901,905,909,913,917,921,925,929,
933,937,941,945,949,953,955,1377,1379,1381,1383,1385,1387,1389, mul1391.In
one embodiment the antibody or fragment thereof comprises a heavy chain
variable region
encoded by a polynucleotide selected from the group consisting of SEQ ID NOs:
722, 726,
730, 734, 738, 742, 746, 750, 754, 758, 762, 766, 770, 774, 778, 782, 786,
790, 794, 798,
802, 806, 810, 814, 818, 822, 826, 830, 834, 838, 842, 846, 850, 854, 858,
862, 866, 870,
874, 878, 882, 886, 890, 894, 898, 902, 906, 910, 914, 918, 922, 926, 930,
934, 938, 942,
946, 950, 954, 958, 1378, 1380, 1382, 1384, 1386, 1388, 1390, and 1392. In one
embodiment
the antibody or fragment thereof comprises a light chain variable region
encoded by a
polynucleotide sequence selected from the group consisting of SEQ ID NOs: 721,
725, 729,
733, 737, 741, 745, 749, 753, 757, 761, 765, 769, 773, 777, 781, 785, 789,
793, 797, 801,
805, 809, 813, 817, 821, 825, 829, 833, 837, 841, 845, 849, 853, 857, 861,
865, 869, 873,
877, 881, 885, 889, 893, 897, 901, 905, 909, 913, 917, 921, 925, 929, 933,
937, 941, 945,
949, 953, 955, 1377, 1379, 1381, 1383, 1385, 1387, 1389, and 1391 and a heavy
chain
variable region encoded by a polynucleotide sequence selected from the group
consisting of
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SEQ ID NOs: 722, 726, 730, 734, 738, 742, 746, 750, 754, 758, 762, 766, 770,
774, 778, 782,
786, 790, 794, 798, 802, 806, 810, 814, 818, 822, 826, 830, 834, 838, 842,
846, 850, 854,
858, 862, 866, 870, 874, 878, 882, 886, 890, 894, 898, 902, 906, 910, 914,
918, 922, 926,
930, 934, 938, 942, 946, 950, 954, 958, 1378, 1380, 1382, 1384, 1386, 1388,
1390, and 1392.
In one embodiment the antibody or fragment thereof comprises a combination of
light chain
variable region and a heavy chain variable region selected from the group
consisting of a
light chain variable region encoded by a light chain variable region encoded
by a
polynucleotide sequence comprising SEQ ID NO: 721 and a heavy chain variable
region
encoded by a polynucleotide sequence comprising SEQ ID NO: 722; a light chain
variable
region encoded by a polynucleotide sequence comprising SEQ ID NO: 725 and a
heavy chain
variable region encoded by a polynucleotide sequence comprising SEQ ID NO:
726; a light
chain variable region encoded by a polynucleotide sequence comprising SEQ ID
NO: 729
and a heavy chain variable region encoded by a polynucleotide sequence
comprising SEQ ID
NO: 730; a light chain variable region encoded by a polynucleotide sequence
comprising
SEQ ID NO: 733 and a heavy chain variable region encoded by a polynucleotide
sequence
comprising SEQ ID NO: 734; a light chain variable region encoded by a
polynucleotide
sequence comprising SEQ ID NO: 737 and a heavy chain variable region encoded
by a
polynucleotide sequence comprising SEQ ID NO: 738; a light chain variable
region encoded
by a polynucleotide sequence comprising SEQ ID NO: 741 and a heavy chain
variable region
encoded by a polynucleotide sequence comprising SEQ ID NO: 742; a light chain
variable
region encoded by a polynucleotide sequence comprising SEQ ID NO: 745 and a
heavy chain
variable region encoded by a polynucleotide sequence comprising SEQ ID NO:
746; a light
chain variable region encoded by a polynucleotide sequence comprising SEQ ID
NO: 749
and a heavy chain variable region encoded by a polynucleotide sequence
comprising SEQ ID
NO: 750; a light chain variable region encoded by a polynucleotide sequence
comprising
SEQ ID NO: 753 and a heavy chain variable region encoded by a polynucleotide
sequence
comprising SEQ ID NO: 754; a light chain variable region encoded by a
polynucleotide
sequence comprising SEQ ID NO: 757 and a heavy chain variable region encoded
by a
polynucleotide sequence comprising SEQ ID NO: 758; a light chain variable
region encoded
by a polynucleotide sequence comprising SEQ ID NO: 761 and a heavy chain
variable region
encoded by a polynucleotide sequence comprising SEQ ID NO: 762; a light chain
variable
region encoded by a polynucleotide sequence comprising SEQ ID NO: 765 and a
heavy chain
variable region encoded by a polynucleotide sequence comprising SEQ ID NO:
766; a light
chain variable region encoded by a polynucleotide sequence comprising SEQ ID
NO: 769
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and a heavy chain variable region encoded by a polynucleotide sequence
comprising SEQ ID
NO: 770; a light chain variable region encoded by a polynucleotide sequence
comprising
SEQ ID NO: 773 and a heavy chain variable region encoded by a polynucleotide
sequence
comprising SEQ ID NO: 774; a light chain variable region encoded by a
polynucleotide
sequence comprising SEQ ID NO: 777 and a heavy chain variable region encoded
by a
polynucleotide sequence comprising SEQ ID NO: 778; a light chain variable
region encoded
by a polynucleotide sequence comprising SEQ ID NO: 781 and a heavy chain
variable region
encoded by a polynucleotide sequence comprising SEQ ID NO: 782; a light chain
variable
region encoded by a polynucleotide sequence comprising SEQ ID NO: 785 and a
heavy chain
variable region encoded by a polynucleotide sequence comprising SEQ ID NO:
786; a light
chain variable region encoded by a polynucleotide sequence comprising SEQ ID
NO: 789
and a heavy chain variable region encoded by a polynucleotide sequence
comprising SEQ ID
NO: 790; a light chain variable region encoded by a polynucleotide sequence
comprising
SEQ ID NO: 793 and a heavy chain variable region encoded by a polynucleotide
sequence
comprising SEQ ID NO: 794; a light chain variable region encoded by a
polynucleotide
sequence comprising SEQ ID NO: 797 and a heavy chain variable region encoded
by a
polynucleotide sequence comprising SEQ ID NO: 798; a light chain variable
region encoded
by a polynucleotide sequence comprising SEQ ID NO: 801 and a heavy chain
variable region
encoded by a polynucleotide sequence comprising SEQ ID NO: 802; a light chain
variable
region encoded by a polynucleotide sequence comprising SEQ ID NO: 805 and a
heavy chain
variable region encoded by a polynucleotide sequence comprising SEQ ID NO:
806; a light
chain variable region encoded by a polynucleotide sequence comprising SEQ ID
NO: 809
and a heavy chain variable region encoded by a polynucleotide sequence
comprising SEQ ID
NO: 810; a light chain variable region encoded by a polynucleotide sequence
comprising
SEQ ID NO: 813 and a heavy chain variable region encoded by a polynucleotide
sequence
comprising SEQ ID NO: 814; a light chain variable region encoded by a
polynucleotide
sequence comprising SEQ ID NO: 817 and a heavy chain variable region encoded
by a
polynucleotide sequence comprising SEQ ID NO: 818; a light chain variable
region encoded
by a polynucleotide sequence comprising SEQ ID NO: 821 and a heavy chain
variable region
encoded by a polynucleotide sequence comprising SEQ ID NO: 822; a light chain
variable
region encoded by a polynucleotide sequence comprising SEQ ID NO: 825 and a
heavy chain
variable region encoded by a polynucleotide sequence comprising SEQ ID NO:
826; a light
chain variable region encoded by a polynucleotide sequence comprising SEQ ID
NO: 829
and a heavy chain variable region encoded by a polynucleotide sequence
comprising SEQ ID
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NO: 830; a light chain variable region encoded by a polynucleotide sequence
comprising
SEQ ID NO: 833 and a heavy chain variable region encoded by a polynucleotide
sequence
comprising SEQ ID NO: 834; a light chain variable region encoded by a
polynucleotide
sequence comprising SEQ ID NO: 837 and a heavy chain variable region encoded
by a
polynucleotide sequence comprising SEQ ID NO: 838; a light chain variable
region encoded
by a polynucleotide sequence comprising SEQ ID NO: 841 and a heavy chain
variable region
encoded by a polynucleotide sequence comprising SEQ ID NO: 842; a light chain
variable
region encoded by a polynucleotide sequence comprising SEQ ID NO: 845 and a
heavy chain
variable region encoded by a polynucleotide sequence comprising SEQ ID NO:
846; a light
chain variable region encoded by a polynucleotide sequence comprising SEQ ID
NO: 849
and a heavy chain variable region encoded by a polynucleotide sequence
comprising SEQ ID
NO: 850; a light chain variable region encoded by a polynucleotide sequence
comprising
SEQ ID NO: 853 and a heavy chain variable region encoded by a polynucleotide
sequence
comprising SEQ ID NO: 854; a light chain variable region encoded by a
polynucleotide
sequence comprising SEQ ID NO: 857 and a heavy chain variable region encoded
by a
polynucleotide sequence comprising SEQ ID NO: 858; a light chain variable
region encoded
by a polynucleotide sequence comprising SEQ ID NO: 861 and a heavy chain
variable region
encoded by a polynucleotide sequence comprising SEQ ID NO: 862; a light chain
variable
region encoded by a polynucleotide sequence comprising SEQ ID NO: 865 and a
heavy chain
variable region encoded by a polynucleotide sequence comprising SEQ ID NO:
866; a light
chain variable region encoded by a polynucleotide sequence comprising SEQ ID
NO: 869
and a heavy chain variable region encoded by a polynucleotide sequence
comprising SEQ ID
NO: 870; a light chain variable region encoded by a polynucleotide sequence
comprising
SEQ ID NO: 873 and a heavy chain variable region encoded by a polynucleotide
sequence
comprising SEQ ID NO: 874; a light chain variable region encoded by a
polynucleotide
sequence comprising SEQ ID NO: 877 and a heavy chain variable region encoded
by a
polynucleotide sequence comprising SEQ ID NO: 878; a light chain variable
region encoded
by a polynucleotide sequence comprising SEQ ID NO: 881 and a heavy chain
variable region
encoded by a polynucleotide sequence comprising SEQ ID NO: 882; a light chain
variable
region encoded by a polynucleotide sequence comprising SEQ ID NO: 885 and a
heavy chain
variable region encoded by a polynucleotide sequence comprising SEQ ID NO:
886; a light
chain variable region encoded by a polynucleotide sequence comprising SEQ ID
NO: 889
and a heavy chain variable region encoded by a polynucleotide sequence
comprising SEQ ID
NO: 890; a light chain variable region encoded by a polynucleotide sequence
comprising
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SEQ ID NO: 893 and a heavy chain variable region encoded by a polynucleotide
sequence
comprising SEQ ID NO: 894; a light chain variable region encoded by a
polynucleotide
sequence comprising SEQ ID NO: 897 and a heavy chain variable region encoded
by a
polynucleotide sequence comprising SEQ ID NO: 898; a light chain variable
region encoded
by a polynucleotide sequence comprising SEQ ID NO: 901 and a heavy chain
variable region
encoded by a polynucleotide sequence comprising SEQ ID NO: 902; a light chain
variable
region encoded by a polynucleotide sequence comprising SEQ ID NO: 905 and a
heavy chain
variable region encoded by a polynucleotide sequence comprising SEQ ID NO:
906; a light
chain variable region encoded by a polynucleotide sequence comprising SEQ ID
NO: 909
and a heavy chain variable region encoded by a polynucleotide sequence
comprising SEQ ID
NO: 910; a light chain variable region encoded by a polynucleotide sequence
comprising
SEQ ID NO: 913 and a heavy chain variable region encoded by a polynucleotide
sequence
comprising SEQ ID NO: 914; a light chain variable region encoded by a
polynucleotide
sequence comprising SEQ ID NO: 917 and a heavy chain variable region encoded
by a
polynucleotide sequence comprising SEQ ID NO: 918; a light chain variable
region encoded
by a polynucleotide sequence comprising SEQ ID NO: 921 and a heavy chain
variable region
encoded by a polynucleotide sequence comprising SEQ ID NO: 922; a light chain
variable
region encoded by a polynucleotide sequence comprising SEQ ID NO: 925 and a
heavy chain
variable region encoded by a polynucleotide sequence comprising SEQ ID NO:
926; a light
chain variable region encoded by a polynucleotide sequence comprising SEQ ID
NO: 929
and a heavy chain variable region encoded by a polynucleotide sequence
comprising SEQ ID
NO: 930; a light chain variable region encoded by a polynucleotide sequence
comprising
SEQ ID NO: 933 and a heavy chain variable region encoded by a polynucleotide
sequence
comprising SEQ ID NO: 934; a light chain variable region encoded by a
polynucleotide
sequence comprising SEQ ID NO: 937 and a heavy chain variable region encoded
by a
polynucleotide sequence comprising SEQ ID NO: 938; a light chain variable
region encoded
by a polynucleotide sequence comprising SEQ ID NO: 941 and a heavy chain
variable region
encoded by a polynucleotide sequence comprising SEQ ID NO: 942; a light chain
variable
region encoded by a polynucleotide sequence comprising SEQ ID NO: 945 and a
heavy chain
variable region encoded by a polynucleotide sequence comprising SEQ ID NO:
946; a light
chain variable region encoded by a polynucleotide sequence comprising SEQ ID
NO: 949
and a heavy chain variable region encoded by a polynucleotide sequence
comprising SEQ ID
NO: 950; a light chain variable region encoded by a polynucleotide sequence
comprising
SEQ ID NO: 953 and a heavy chain variable region encoded by a polynucleotide
sequence
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comprising SEQ ID NO: 954; a light chain variable region encoded by a
polynucleotide
sequence comprising SEQ ID NO: 957 and a heavy chain variable region encoded
by a
polynucleotide sequence comprising SEQ ID NO: 958; a light chain variable
region encoded
by a polynucleotide sequence comprising SEQ ID NO: 1377 and a heavy chain
variable
region encoded by a polynucleotide sequence comprising SEQ ID NO: 1378; a
light chain
variable region encoded by a polynucleotide sequence comprising SEQ ID NO:
1379 and a
heavy chain variable region encoded by a polynucleotide sequence comprising
SEQ ID NO:
1380; a light chain variable region encoded by a polynucleotide sequence
comprising SEQ ID
NO: 1381 and a heavy chain variable region encoded by a polynucleotide
sequence
comprising SEQ ID NO: 1382; a light chain variable region encoded by a
polynucleotide
sequence comprising SEQ ID NO: 1383 and a heavy chain variable region encoded
by a
polynucleotide sequence comprising SEQ ID NO: 1384; a light chain variable
region encoded
by a polynucleotide sequence comprising SEQ ID NO: 1385 and a heavy chain
variable
region encoded by a polynucleotide sequence comprising SEQ ID NO: 1386; a
light chain
variable region encoded by a polynucleotide sequence comprising SEQ ID NO:
1387 and a
heavy chain variable region encoded by a polynucleotide sequence comprising
SEQ ID NO:
1388; a light chain variable region encoded by a polynucleotide sequence
comprising SEQ ID
NO: 1389 and a heavy chain variable region encoded by a polynucleotide
sequence
comprising SEQ ID NO: 1390; and a light chain variable region encoded by a
polynucleotide
sequence comprising SEQ ID NO: 1391 and a heavy chain variable region encoded
by a
polynucleotide sequence comprising SEQ ID NO: 1392.
[0206] Some antigen binding proteins comprise a variable light domain and a
variable heavy
domain as listed in one of the rows for one of the antibodies listed in TABLE
3. In some
instances, the antigen binding protein comprises two identical variable light
domains and two
identical variable heavy domains from one of the antibodies listed in TABLE 3.
Some
antigen binding proteins that are provided comprise a variable light domain
and a variable
heavy domain as listed in one of the rows for one of the antibodies listed in
TABLE 3, except
that one or both of the domains differs from the sequence specified in the
table at only 1, 2, 3,
4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid residues, wherein each
such sequence
difference is independently either a single amino acid deletion, insertion or
substitution, with
the deletions, insertions and/or substitutions resulting in no more than 1, 2,
3, 4, 5, 6, 7, 8, 9,
10, 11, 12, 13, 14 or 15 amino acid changes relative to the variable domain
sequences
specified in TABLE 3. In one embodiment, the antigen binding protein comprises
a variable
region sequence from Table 3, but with the N-terminal methionine deleted.
Other antigen
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binding proteins also comprise a variable light domain and a variable heavy
domain as listed
in one of the rows for one of the antibodies listed in TABLE 3, except that
one or both of the
domains differs from the sequence specified in the table in that the heavy
chain variable
domain and/or light chain variable domain comprises or consists of a sequence
of amino
acids that has at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%
sequence
identity to the amino acid sequences of the heavy chain variable domain or
light chain
variable domain sequences as specified in TABLE 3.
[0207] In another aspect, the antigen binding protein consists just of a
variable light or
variable heavy domain from an antibody listed in TABLE 3. In still another
aspect, the
antigen binding protein comprises two or more of the same variable heavy
domains or two or
more of the same variable light domains from those listed in TABLE 3. Such
domain
antibodies can be fused together or joined via a linker as described in
greater detail below.
The domain antibodies can also be fused or linked to one or more molecules to
extend the
half-life (e.g., PEG or albumin).
[0208] In certain embodiments it is desired that the antigen binding protein
is an antibody
with reduced viscosity. Such of antigen binding proteins can be produced by
modifying
sequences in framework regions and/or the Fc domain that are shown to be
associated with
high viscosity.
[0209] Such reduced-viscosity antigen binding proteins included antibodies
wherein:
[0210] the VH111-18 germline subfamily sequence comprises one or more
substitutions
selected from 82R, 94S, and 95R;
[0211] the VH313-33 germline subfamily sequence comprises one or more of
substitutions
1E, 17G, and 85A;
[0212] the VK31L16 germline subfamily sequence comprises one or more
substitutions
selected from 4L, 13L, 76D, 95R, 97E, and 98P;
[0213] the VK31L6 germline subfamily sequence comprises one or more
substitutions
selected from 76D and 95R;
[0214] the Fc domain sequence comprises one or more substitutions selected
from 253A,
440K, and 439E; and
[0215] the Fc domain C-terminus comprises a sequence selected from KP, KKP,
KKKP, and
E..
[0216] All of the foregoing preferred viscosity-reducing amino acid
substitutions in variable
regions are identified by the Aho numbering system. All viscosity-reducing
residues in
conserved regions including Fc are identified by the EU numbering system.
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[0217]
[0218] Other antigen binding proteins that are provided are variants of
antibodies formed by
combination of the heavy and light chains shown in TABLE 3 and comprise light
and/or
heavy chains that each have at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%,
98% or
99% identity to the amino acid sequences of these chains. In some instances,
such antibodies
include at least one heavy chain and one light chain, whereas in other
instances the variant
forms contain two identical light chains and two identical heavy chains.
[0219] The various combinations of heavy chain variable regions may be
combined with any
of the various combinations of light chain variable regions.
[0220] In a further embodiment, the isolated antigen binding protein provided
herein is a
human antibody comprising a sequence as set forth in TABLE 3 and is of the
IgGi-, IgG2-
IgG3- or IgG4-type.
[0221] The antigen binding proteins disclosed herein are polypeptides into
which one or
more CDRs are grafted, inserted and/or joined. An antigen binding protein can
have 1, 2, 3, 4,
or 6 CDRs. An antigen binding protein thus can have, for example, one heavy
chain CDR1
("CDRH1"), and/or one heavy chain CDR2 ("CDRH2"), and/or one heavy chain CDR3
("CDRH3"), and/or one light chain CDR1 ("CDRL1"), and/or one light chain CDR2
("CDRL2"), and/or one light chain CDR3 ("CDRL3"). Some antigen binding
proteins
include both a CDRH3 and a CDRL3. Specific light and heavy chain CDRs are
identified in
TABLEs 4A and 4B, respectively.
[0222] Complementarity determining regions (CDRs) and framework regions (FR)
of a given
antibody may be identified using the system described by Kabat et al. in
Sequences of
Proteins of Immunological Interest, 5th Ed., US Dept. of Health and Human
Services, PHS,
NIH, NIH Publication no. 91-3242, 1991. Certain antibodies that are disclosed
herein
comprise one or more amino acid sequences that are identical or have
substantial sequence
identity to the amino acid sequences of one or more of the CDRs presented in
TABLES 4A
and 4B. These CDRs use the system described by Kabat et al. as noted above.
[0223] The structure and properties of CDRs within a naturally occurring
antibody has been
described, supra. Briefly, in a traditional antibody, the CDRs are embedded
within a
framework in the heavy and light chain variable region where they constitute
the regions
responsible for antigen binding and recognition. A variable region comprises
at least three
heavy or light chain CDRs, see, supra (Kabat etal., 1991, Sequences of
Proteins of
Immunological Interest, Public Health Service N.I.H., Bethesda, MD; see also
Chothia and
Lesk, 1987,1 Mol. Biol. 196:901-917; Chothia etal., 1989, Nature 342: 877-
883), within a
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framework region (designated framework regions 1-4, FR1, FR2, FR3, and FR4, by
Kabat et
al., 1991, supra; see also Chothia and Lesk, 1987, supra). The CDRs provided
herein,
however, may not only be used to define the antigen binding domain of a
traditional antibody
structure, but may be embedded in a variety of other polypeptide structures,
as described
herein.
[0224] In one embodiment the antibody or fragment thereof comprises a CDRL1, a
CDRL2,
a CDRL3, a CDRH1, a CDRH2, and a CDRH3. In one embodiment the antibody or
fragment
thereof comprises a CDRL1 comprising a sequence selected from the group
consisting of
SEQ ID NOs: 4, 10, 16, 22, 28, 34, 40, 46, 52, 58, 64, 70, 76, 82, 88, 94,
100, 106, 112, 118,
124, 130, 136, 142, 148, 154, 160, 166, 172, 178, 184, 190, 196, 202, 208,
214, 220, 226,
232, 238, 244, 250, 256, 262, 268, 274, 280, 286, 292, 298, 304, 310, 316,
322, 328, 334,
340, 346, 352, 358, 1290, 1300, 1310, 1320, 1330, 1340, and 1350. In one
embodiment the
antibody or fragment thereof comprises a CDRL2 comprising a sequence selected
from the
group consisting of SEQ ID NOs: 5, 11, 17, 23, 29, 35, 41, 47, 53, 59, 65, 71,
77, 83, 89, 95,
101, 107, 113, 119, 125, 131, 137, 143, 149, 155, 161, 167, 173, 179, 185,
191, 197, 203,
209, 215, 221, 227, 233, 239, 245, 251, 257, 263, 269, 275, 281, 287, 293,
299, 305, 311,
317, 323, 329, 335, 341, 347, 353, 359, 1291, 1301, 1311, 1321, 1331, 1341,
and 1351. In
one embodiment the antibody or fragment thereof comprises a CDRL3 comprising a
sequence selected from the group consisting of SEQ ID NOs: 6, 12, 18, 24, 30,
36, 42, 48, 54,
60, 66, 72, 78, 84, 90, 96, 102, 108, 114, 120, 126, 132, 138, 144, 150, 156,
162, 168, 174,
180, 186, 192, 198, 204, 210, 216, 222, 228, 234, 240, 246, 252, 258, 264,
270, 276, 282,
288, 294, 300, 306, 312, 318, 324, 330, 336, 342, 348, 354, 360, 1292, 1302,
1312, 1322,
1332, 1342, and 1352. In one embodiment the antibody or fragment thereof
comprises a
CDRH1 comprising a sequence selected from the group consisting of SEQ ID NOs:
364, 370,
376, 382, 388, 394, 400, 406, 412, 418, 424, 430, 436, 442, 448, 454, 460,
466, 472, 478,
484, 490, 496, 502, 508, 514, 520, 526, 532, 538, 544, 550, 556, 562, 568,
574, 580, 586,
592, 598, 604, 610, 616, 622, 628, 634, 640, 646, 652, 658, 664, 670, 676,
682, 688, 694,
700, 706, 712, 718, 1293, 1303, 1313, 1323, 1333, 1343, and 1353. In one
embodiment the
antibody or fragment thereof comprises a CDRH2 comprising a sequence selected
from the
group consisting of SEQ ID NOs: 365, 371, 377, 383, 389, 395, 401, 407, 413,
419, 425, 431,
437, 443, 449, 455, 461, 467, 473, 479, 485, 491, 497, 503, 509, 515, 521,
527, 533, 539,
545, 551, 557, 563, 569, 575, 581, 587, 593, 599, 605, 611, 617, 623, 629,
635, 641, 647,
653, 659, 665, 671, 677, 683, 689, 695, 701, 707, 713, 719, 1294, 1304, 1314,
1324, 1334,
1344, and 1354. In one embodiment the antibody or fragment thereof comprises a
CDRH3
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comprising a sequence selected from the group consisting of SEQ ID NOs: 366,
372, 378,
384, 390, 396, 402, 408, 414, 420, 426, 432, 438, 444, 450, 456, 462, 468,
474, 480, 486,
492, 498, 504, 510, 516, 522, 528, 534, 540, 546, 552, 558, 564, 570, 576,
582, 588, 594,
600, 606, 612, 618, 624, 630, 636, 642, 648, 654, 660, 666, 672, 678, 684,
690, 696, 702,
708, 714, 720, 1295, 1305, 1315, 1325, 1335, 1345, and 1355. In one embodiment
the
antibody or fragment thereof comprises a CDRL1, a CDRL2, a CDRL3, a CDRH1, a
CDRH2, and a CDRH3, wherein each CDRL1, CDRL2, CDRL3, CDRH1, CDRH2, and
CDRH3, respectively, comprises a sequence selected from the group consisting
of SEQ ID
NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 364, SEQ ID NO: 365, and SEQ ID
NO:
366; SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 370, SEQ ID NO:
371,
and SEQ ID NO: 372; SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO:
376,
SEQ ID NO: 377, and SEQ ID NO: 378; SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO:
24,
SEQ ID NO: 382, SEQ ID NO: 383, and SEQ ID NO: 384; SEQ ID NO: 28, SEQ ID NO:
29,
SEQ ID NO: 30, SEQ ID NO: 388, SEQ ID NO: 389, and SEQ ID NO: 390; SEQ ID NO:
34,
SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 394, SEQ ID NO: 395, and SEQ ID NO:
396;
SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO: 42, SEQ ID NO: 400, SEQ ID NO: 401,
and
SEQ ID NO: 402; SEQ ID NO: 46, SEQ ID NO: 47, SEQ ID NO: 48, SEQ ID NO: 406,
SEQ
ID NO: 407, and SEQ ID NO: 408; SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54,
SEQ
ID NO: 412, SEQ ID NO: 413, and SEQ ID NO: 414; SEQ ID NO: 58, SEQ ID NO: 59,
SEQ
ID NO: 60, SEQ ID NO: 418, SEQ ID NO: 419, and SEQ ID NO: 420; SEQ ID NO: 64,
SEQ
ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 424, SEQ ID NO: 425, and SEQ ID NO: 426;
SEQ
ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 430, SEQ ID NO: 431, and
SEQ
ID NO: 432; SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, SEQ ID NO: 436, SEQ
ID
NO: 437, and SEQ ID NO: 438; SEQ ID NO: 82, SEQ ID NO: 83, SEQ ID NO: 84, SEQ
ID
NO: 442, SEQ ID NO: 443, and SEQ ID NO: 444; SEQ ID NO: 88, SEQ ID NO: 89, SEQ
ID
NO: 90, SEQ ID NO: 448, SEQ ID NO: 449, and SEQ ID NO: 450; SEQ ID NO: 94, SEQ
ID
NO: 95, SEQ ID NO: 96, SEQ ID NO: 454, SEQ ID NO: 455, and SEQ ID NO: 456; SEQ
ID
NO: 100, SEQ ID NO: 101, SEQ ID NO: 102, SEQ ID NO: 460, SEQ ID NO: 461, and
SEQ
ID NO: 462; SEQ ID NO: 106, SEQ ID NO: 107, SEQ ID NO: 108, SEQ ID NO: 466,
SEQ
ID NO: 467, and SEQ ID NO: 468; SEQ ID NO: 112, SEQ ID NO: 113, SEQ ID NO:
114,
SEQ ID NO: 472, SEQ ID NO: 473, and SEQ ID NO: 474; SEQ ID NO: 118, SEQ ID NO:
119, SEQ ID NO: 120, SEQ ID NO: 478, SEQ ID NO: 479, and SEQ ID NO: 480; SEQ
ID
NO: 124, SEQ ID NO: 125, SEQ ID NO: 126, SEQ ID NO: 484, SEQ ID NO: 485, and
SEQ
ID NO: 486; SEQ ID NO: 130, SEQ ID NO: 131, SEQ ID NO: 132, SEQ ID NO: 490,
SEQ
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ID NO: 491, and SEQ ID NO: 492; SEQ ID NO: 136, SEQ ID NO: 137, SEQ ID NO:
138,
SEQ ID NO: 496, SEQ ID NO: 497, and SEQ ID NO: 498; SEQ ID NO: 142, SEQ ID NO:
143, SEQ ID NO: 144, SEQ ID NO: 502, SEQ ID NO: 503, and SEQ ID NO: 504; SEQ
ID
NO: 148, SEQ ID NO: 149, SEQ ID NO: 150, SEQ ID NO: 508, SEQ ID NO: 509, and
SEQ
ID NO: 510; SEQ ID NO: 154, SEQ ID NO: 155, SEQ ID NO: 156, SEQ ID NO: 514,
SEQ
ID NO: 515, and SEQ ID NO: 516; SEQ ID NO: 160, SEQ ID NO: 161, SEQ ID NO:
162,
SEQ ID NO: 520, SEQ ID NO: 521, and SEQ ID NO: 522; SEQ ID NO: 166, SEQ ID NO:
167, SEQ ID NO: 168, SEQ ID NO: 526, SEQ ID NO: 527, and SEQ ID NO: 528; SEQ
ID
NO: 172, SEQ ID NO: 173, SEQ ID NO: 174, SEQ ID NO: 532, SEQ ID NO: 533, and
SEQ
ID NO: 534; SEQ ID NO: 178, SEQ ID NO: 179, SEQ ID NO: 180, SEQ ID NO: 538,
SEQ
ID NO: 539, and SEQ ID NO: 540; SEQ ID NO: 184, SEQ ID NO: 185, SEQ ID NO:
186,
SEQ ID NO: 544, SEQ ID NO: 545, and SEQ ID NO: 546; SEQ ID NO: 190, SEQ ID NO:
191, SEQ ID NO: 192, SEQ ID NO: 550, SEQ ID NO: 551, and SEQ ID NO: 552; SEQ
ID
NO: 196, SEQ ID NO: 197, SEQ ID NO: 198, SEQ ID NO: 556, SEQ ID NO: 557, and
SEQ
ID NO: 558; SEQ ID NO: 202, SEQ ID NO: 203, SEQ ID NO: 204, SEQ ID NO: 562,
SEQ
ID NO: 563, and SEQ ID NO: 564; SEQ ID NO: 208, SEQ ID NO: 209, SEQ ID NO:
210,
SEQ ID NO: 568, SEQ ID NO: 569, and SEQ ID NO: 570; SEQ ID NO: 214, SEQ ID NO:
215, SEQ ID NO: 216, SEQ ID NO: 574, SEQ ID NO: 575, and SEQ ID NO: 576; SEQ
ID
NO: 220, SEQ ID NO: 221, SEQ ID NO: 222, SEQ ID NO: 580, SEQ ID NO: 581, and
SEQ
ID NO: 582; SEQ ID NO: 226, SEQ ID NO: 227, SEQ ID NO: 228, SEQ ID NO: 586,
SEQ
ID NO: 587, and SEQ ID NO: 588; SEQ ID NO: 232, SEQ ID NO: 233, SEQ ID NO:
234,
SEQ ID NO: 592, SEQ ID NO: 593, and SEQ ID NO: 594; SEQ ID NO: 238, SEQ ID NO:
239, SEQ ID NO: 240, SEQ ID NO: 598, SEQ ID NO: 599, and SEQ ID NO: 600; SEQ
ID
NO: 244, SEQ ID NO: 245, SEQ ID NO: 246, SEQ ID NO: 604, SEQ ID NO: 605, and
SEQ
ID NO: 606; SEQ ID NO: 250, SEQ ID NO: 251, SEQ ID NO: 252, SEQ ID NO: 610,
SEQ
ID NO: 611, and SEQ ID NO: 612; SEQ ID NO: 256, SEQ ID NO: 257, SEQ ID NO:
258,
SEQ ID NO: 616, SEQ ID NO: 617, and SEQ ID NO: 618; SEQ ID NO: 262, SEQ ID NO:
263, SEQ ID NO: 264, SEQ ID NO: 622, SEQ ID NO: 623, and SEQ ID NO: 624; SEQ
ID
NO: 268, SEQ ID NO: 269, SEQ ID NO: 270, SEQ ID NO: 628, SEQ ID NO: 629, and
SEQ
ID NO: 630; SEQ ID NO: 274, SEQ ID NO: 275, SEQ ID NO: 276, SEQ ID NO: 634,
SEQ
ID NO: 635, and SEQ ID NO: 636; SEQ ID NO: 280, SEQ ID NO: 281, SEQ ID NO:
282,
SEQ ID NO: 640, SEQ ID NO: 641, and SEQ ID NO: 642; SEQ ID NO: 286, SEQ ID NO:
287, SEQ ID NO: 288, SEQ ID NO: 646, SEQ ID NO: 647, and SEQ ID NO: 648; SEQ
ID
NO: 292, SEQ ID NO: 293, SEQ ID NO: 294, SEQ ID NO: 652, SEQ ID NO: 653, and
SEQ
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ID NO: 654; SEQ ID NO: 298, SEQ ID NO: 299, SEQ ID NO: 300, SEQ ID NO: 658,
SEQ
ID NO: 659, and SEQ ID NO: 660; SEQ ID NO: 304, SEQ ID NO: 305, SEQ ID NO:
306,
SEQ ID NO: 664, SEQ ID NO: 665, and SEQ ID NO: 666; SEQ ID NO: 310, SEQ ID NO:
311, SEQ ID NO: 312, SEQ ID NO: 670, SEQ ID NO: 671, and SEQ ID NO: 672; SEQ
ID
NO: 316, SEQ ID NO: 317, SEQ ID NO: 318, SEQ ID NO: 676, SEQ ID NO: 677, and
SEQ
ID NO: 678; SEQ ID NO: 322, SEQ ID NO: 323, SEQ ID NO: 324, SEQ ID NO: 682,
SEQ
ID NO: 683, and SEQ ID NO: 684; SEQ ID NO: 328, SEQ ID NO: 329, SEQ ID NO:
330,
SEQ ID NO: 688, SEQ ID NO: 689, and SEQ ID NO: 690; SEQ ID NO: 334, SEQ ID NO:
335, SEQ ID NO: 336, SEQ ID NO: 694, SEQ ID NO: 695, and SEQ ID NO: 696; SEQ
ID
NO: 340, SEQ ID NO: 341, SEQ ID NO: 342, SEQ ID NO: 700, SEQ ID NO: 701, and
SEQ
ID NO: 702; SEQ ID NO: 346, SEQ ID NO: 347, SEQ ID NO: 348, SEQ ID NO: 706,
SEQ
ID NO: 707, and SEQ ID NO: 708; SEQ ID NO: 352, SEQ ID NO: 353, SEQ ID NO:
354,
SEQ ID NO: 712, SEQ ID NO: 713, and SEQ ID NO: 714; SEQ ID NO: 358, SEQ ID NO:
359, SEQ ID NO: 360, SEQ ID NO: 718, SEQ ID NO: 719, and SEQ ID NO: 720; SEQ
ID
NO: 1290, SEQ ID NO: 1291, SEQ ID NO: 1292, SEQ ID NO: 1293, SEQ ID NO: 1294,
and
SEQ ID NO: 1295; SEQ ID NO: 1300, SEQ ID NO: 1301, SEQ ID NO: 1302, SEQ ID NO:
1303, SEQ ID NO: 1304, and SEQ ID NO: 1305; SEQ ID NO: 1310, SEQ ID NO: 1311,
SEQ ID NO: 1312, SEQ ID NO: 1313, SEQ ID NO: 1314, and SEQ ID NO: 1315; SEQ ID
NO: 1320, SEQ ID NO: 1321, SEQ ID NO: 1322, SEQ ID NO: 1323, SEQ ID NO: 1324,
and
SEQ ID NO: 1325; SEQ ID NO: 1330, SEQ ID NO: 1331, SEQ ID NO: 1332, SEQ ID NO:
1333, SEQ ID NO: 1334, and SEQ ID NO: 1335; SEQ ID NO: 1340, SEQ ID NO: 1341,
SEQ ID NO: 1342, SEQ ID NO: 1343, SEQ ID NO: 1344, and SEQ ID NO: 1345; SEQ ID
NO: 1350, SEQ ID NO: 1351, SEQ ID NO: 1352, SEQ ID NO: 1353, SEQ ID NO: 1354,
and
SEQ ID NO: 1355; and SEQ ID NO: 1360, SEQ ID NO: 1361, SEQ ID NO: 1362, SEQ ID
NO: 1363, SEQ ID NO: 1364, and SEQ ID NO: 1365.
[0225] In another aspect, an antigen binding protein includes 1, 2, 3, 4, 5,
or 6 variant forms
of the CDRs listed in TABLES 4A and 4B, each having at least 80%, 85%, 90%,
95%, 96%,
97%, 98%, or 99% sequence identity to a CDR sequence listed in TABLES 4A and
4B. Some
antigen binding proteins include 1, 2, 3, 4, 5, or 6 of the CDRs listed in
TABLES 4A and 4B,
each or collectively differing by no more than 1, 2, 3, 4 or 5 amino acids
from the CDRs
listed in this table.
[0226] In various other embodiments, the antigen binding protein is derived
from such
antibodies. For instance, in one aspect, the antigen binding protein comprises
1, 2, 3, 4, 5 or
all 6 of the CDRs listed in one of the rows for any particular antibody listed
in TABLES 4A
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and 4B. In another aspect, an antigen binding protein includes 1, 2, 3, 4, 5,
or 6 variant forms
of the CDRs listed in one of the rows for an antibody in TABLES 4A and 4B,
each CDR
having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to
a CDR
sequence listed in TABLES 4A and 4B. Some antigen binding proteins include 1,
2, 3, 4, 5,
or 6 of the CDRs listed in one of the rows of TABLES 4A and 4B, each differing
by no more
than 1, 2, 3, 4 or 5 amino acids from the CDRs listed in these tables. In
another aspect, the
antigen binding protein comprises all 6 of the CDRS listed in a row of TABLES
4A and 4B
and the total number of amino acid changes to the CDRs collectively is no more
than 1, 2, 3,
4, or 5 amino acids.
[0227] In one embodiment the antibody or fragment thereof comprises a light
chain
comprising a sequence selected from the group consisting of SEQ ID NOs: 963,
967, 971,
975,979,983,987,991,995,999,1003,1007,1011,1015,1019,1023,1027,1031,1035,
1039,1043,1047,1051,1055,1059,1063,1067,1071,1075,1079,1083,1087,1091,1095,
1099, 1103, 1107, 1111, 1115, 1119, 1123, 1127, 1131, 1135, 1139, 1143, 1147,
1151, 1155,
1159, 1163, 1167, 1171, 1175, 1179, 1183, 1187, 1191, 1195, 1199, 1288, 1298,
1308, 1318,
1328, 1338, 1348, and 1358. In one embodiment the antibody or fragment thereof
comprises
a heavy chain comprising a sequence selected from the group consisting of SEQ
ID NOs:
964, 968, 972, 976, 980, 984, 988, 992, 996, 1000, 1004, 1008, 1012, 1016,
1020, 1024,
1028, 1032, 1036, 1040, 1044, 1048, 1052, 1056, 1060, 1064, 1068, 1072, 1076,
1080, 1084,
1088, 1092, 1096, 1100, 1104, 1108, 1112, 1116, 1120, 1124, 1128, 1132, 1136,
1140, 1144,
1148, 1152, 1156, 1160, 1164, 1168, 1172, 1176, 1180, 1184, 1188, 1192, 1196,
1200, 1289,
1299, 1309, 1319, 1329, 1339, 1349, and 1359. In one embodiment the antibody
or fragment
thereof comprises a light chain comprising a sequence selected from the group
consisting of
SEQ ID NOs: 963, 967, 971, 975, 979, 983, 987, 991, 995, 999, 1003, 1007,
1011, 1015,
1019, 1023, 1027, 1031, 1035, 1039, 1043, 1047, 1051, 1055, 1059, 1063, 1067,
1071, 1075,
1079, 1083, 1087, 1091, 1095, 1099, 1103, 1107, 1111, 1115, 1119, 1123, 1127,
1131, 1135,
1139,1143,1147,1151,1155,1159,1163,1167,1171,1175,1179,1183,1187,1191,1195,
1199, 1288, 1298, 1308, 1318, 1328, 1338, 1348, and 1358 and a heavy chain
comprising a
sequence selected from the group consisting of SEQ ID NOs: 964, 968, 972, 976,
980, 984,
988, 992, 996, 1000, 1004, 1008, 1012, 1016, 1020, 1024, 1028, 1032, 1036,
1040, 1044,
1048, 1052, 1056, 1060, 1064, 1068, 1072, 1076, 1080, 1084, 1088, 1092, 1096,
1100, 1104,
1108, 1112, 1116, 1120, 1124, 1128, 1132, 1136, 1140, 1144, 1148, 1152, 1156,
1160, 1164,
1168, 1172, 1176, 1180, 1184, 1188, 1192, 1196, 1200, 1289, 1299, 1309, 1319,
1329, 1339,
1349, and 1359. In one embodiment the antibody or fragment thereof comprises a
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combination of a light chain and a heavy chain selected from the group
consisting of a light
chain comprising SEQ ID NO: 963 and a heavy chain comprising SEQ ID NO: 964; a
light
chain comprising SEQ ID NO: 967 and a heavy chain comprising SEQ ID NO: 968; a
light
chain comprising SEQ ID NO: 971 and a heavy chain comprising SEQ ID NO: 972; a
light
chain comprising SEQ ID NO: 975 and a heavy chain comprising SEQ ID NO: 976; a
light
chain comprising SEQ ID NO: 979 and a heavy chain comprising SEQ ID NO: 980; a
light
chain comprising SEQ ID NO: 983 and a heavy chain comprising SEQ ID NO: 984; a
light
chain comprising SEQ ID NO: 987 and a heavy chain comprising SEQ ID NO: 988; a
light
chain comprising SEQ ID NO: 991 and a heavy chain comprising SEQ ID NO: 992; a
light
chain comprising SEQ ID NO: 995 and a heavy chain comprising SEQ ID NO: 996; a
light
chain comprising SEQ ID NO: 999 and a heavy chain comprising SEQ ID NO: 1000;
a light
chain comprising SEQ ID NO: 1003 and a heavy chain comprising SEQ ID NO: 1004;
a light
chain comprising SEQ ID NO: 1007 and a heavy chain comprising SEQ ID NO: 1008;
a light
chain comprising SEQ ID NO: 1011 and a heavy chain comprising SEQ ID NO: 1012;
a light
chain comprising SEQ ID NO: 1015 and a heavy chain comprising SEQ ID NO: 1016;
alight
chain comprising SEQ ID NO: 1019 and a heavy chain comprising SEQ ID NO: 1020;
alight
chain comprising SEQ ID NO: 1023 and a heavy chain comprising SEQ ID NO: 1024;
a light
chain comprising SEQ ID NO: 1027 and a heavy chain comprising SEQ ID NO: 1028;
a light
chain comprising SEQ ID NO: 1031 and a heavy chain comprising SEQ ID NO: 1032;
a light
chain comprising SEQ ID NO: 1035 and a heavy chain comprising SEQ ID NO: 1036;
a light
chain comprising SEQ ID NO: 1039 and a heavy chain comprising SEQ ID NO: 1040;
a light
chain comprising SEQ ID NO: 1043 and a heavy chain comprising SEQ ID NO: 1044;
a light
chain comprising SEQ ID NO: 1047 and a heavy chain comprising SEQ ID NO: 1048;
a light
chain comprising SEQ ID NO: 1051 and a heavy chain comprising SEQ ID NO: 1052;
a light
chain comprising SEQ ID NO: 1055 and a heavy chain comprising SEQ ID NO: 1056;
a light
chain comprising SEQ ID NO: 1059 and a heavy chain comprising SEQ ID NO: 1060;
a light
chain comprising SEQ ID NO: 1063 and a heavy chain comprising SEQ ID NO: 1064;
a light
chain comprising SEQ ID NO: 1067 and a heavy chain comprising SEQ ID NO: 1068;
a light
chain comprising SEQ ID NO: 1071 and a heavy chain comprising SEQ ID NO: 1072;
a light
chain comprising SEQ ID NO: 1075 and a heavy chain comprising SEQ ID NO: 1076;
a light
chain comprising SEQ ID NO: 1079 and a heavy chain comprising SEQ ID NO: 1080;
alight
chain comprising SEQ ID NO: 1083 and a heavy chain comprising SEQ ID NO: 1084;
a light
chain comprising SEQ ID NO: 1087 and a heavy chain comprising SEQ ID NO: 1088;
alight
chain comprising SEQ ID NO: 1091 and a heavy chain comprising SEQ ID NO: 1092;
a light
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chain comprising SEQ ID NO: 1095 and a heavy chain comprising SEQ ID NO: 1096;
a light
chain comprising SEQ ID NO: 1099 and a heavy chain comprising SEQ ID NO: 1100;
a light
chain comprising SEQ ID NO: 1103 and a heavy chain comprising SEQ ID NO: 1104;
a light
chain comprising SEQ ID NO: 1107 and a heavy chain comprising SEQ ID NO: 1108;
a light
chain comprising SEQ ID NO: 1111 and a heavy chain comprising SEQ ID NO: 1112;
a light
chain comprising SEQ ID NO: 1115 and a heavy chain comprising SEQ ID NO: 1116;
a light
chain comprising SEQ ID NO: 1119 and a heavy chain comprising SEQ ID NO: 1120;
a light
chain comprising SEQ ID NO: 1123 and a heavy chain comprising SEQ ID NO: 1124;
a light
chain comprising SEQ ID NO: 1127 and a heavy chain comprising SEQ ID NO: 1128;
a light
chain comprising SEQ ID NO: 1131 and a heavy chain comprising SEQ ID NO: 1132;
a light
chain comprising SEQ ID NO: 1135 and a heavy chain comprising SEQ ID NO: 1136;
a light
chain comprising SEQ ID NO: 1139 and a heavy chain comprising SEQ ID NO: 1140;
a light
chain comprising SEQ ID NO: 1143 and a heavy chain comprising SEQ ID NO: 1144;
a light
chain comprising SEQ ID NO: 1147 and a heavy chain comprising SEQ ID NO: 1148;
a light
chain comprising SEQ ID NO: 1151 and a heavy chain comprising SEQ ID NO: 1152;
a light
chain comprising SEQ ID NO: 1155 and a heavy chain comprising SEQ ID NO: 1156;
a light
chain comprising SEQ ID NO: 1159 and a heavy chain comprising SEQ ID NO: 1160;
a light
chain comprising SEQ ID NO: 1163 and a heavy chain comprising SEQ ID NO: 1164;
a light
chain comprising SEQ ID NO: 1167 and a heavy chain comprising SEQ ID NO: 1168;
a light
chain comprising SEQ ID NO: 1171 and a heavy chain comprising SEQ ID NO: 1172;
a light
chain comprising SEQ ID NO: 1175 and a heavy chain comprising SEQ ID NO: 1176;
a light
chain comprising SEQ ID NO: 1179 and a heavy chain comprising SEQ ID NO: 1180;
a light
chain comprising SEQ ID NO: 1183 and a heavy chain comprising SEQ ID NO: 1184;
a light
chain comprising SEQ ID NO: 1187 and a heavy chain comprising SEQ ID NO: 1188;
a light
chain comprising SEQ ID NO: 1191 and a heavy chain comprising SEQ ID NO: 1192;
a light
chain comprising SEQ ID NO: 1195 and a heavy chain comprising SEQ ID NO: 1196;
a light
chain comprising SEQ ID NO: 1199 and a heavy chain comprising SEQ ID NO: 1200;
a light
chain comprising SEQ ID NO: 1288 and a heavy chain comprising SEQ ID NO: 1289;
a light
chain comprising SEQ ID NO: 1298 and a heavy chain comprising SEQ ID NO: 1299;
a light
chain comprising SEQ ID NO: 1308 and a heavy chain comprising SEQ ID NO: 1309;
a light
chain comprising SEQ ID NO: 1318 and a heavy chain comprising SEQ ID NO: 1319;
a light
chain comprising SEQ ID NO: 1328 and a heavy chain comprising SEQ ID NO: 1329;
a light
chain comprising SEQ ID NO: 1338 and a heavy chain comprising SEQ ID NO: 1339;
a light
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chain comprising SEQ ID NO: 1348 and a heavy chain comprising SEQ ID NO: 1349;
and a
light chain comprising SEQ ID NO: 1358 and a heavy chain comprising SEQ ID NO:
1359.
[0228] In one embodiment the antibody or fragment thereof comprises a light
chain encoded
by a polynucleotide sequence selected from the group consisting of SEQ ID NOs:
961, 965,
969, 973, 977, 981, 985, 989, 993, 997, 1001, 1005, 1009, 1013, 1017, 1021,
1025, 1029,
1033,1037,1041,1045,1049,1053,1057,1061,1065,1069,1073,1077,1081,1085,1089,
1093,1097,1101,1105,1109,1113,1117,1121,1125,1129,1133,1137,1141,1145,1149,
1153,1157,1161,1165,1169,1173,1177,1181,1185,1189,1193,1197,1361,1363,1365,
1367, 1369, 1371, 1373, and 1375. In one embodiment the antibody or fragment
thereof
comprises a heavy chain encoded by a polynucleotide sequence selected from the
group
consisting of SEQ ID NOs: 962, 966, 970, 974, 978, 982, 986, 990, 994, 998,
1002, 1006,
1010, 1014, 1018, 1022, 1026, 1030, 1034, 1038, 1042, 1046, 1050, 1054, 1058,
1062, 1066,
1070, 1074, 1078, 1082, 1086, 1090, 1094, 1098, 1102, 1106, 1110, 1114, 1118,
1122, 1126,
1130, 1134, 1138, 1142, 1146, 1150, 1154, 1158, 1162, 1166, 1170, 1174, 1178,
1182, 1186,
1190, 1194, 1198, 1362, 1364, 1366, 1368, 1370, 1372, 1374, and 1376. In one
embodiment
the antibody or fragment thereof comprises a light chain encoded by a
polynucleotide
sequence selected from the group consisting of SEQ ID NOs: 961, 965, 969, 973,
977, 981,
985,989,993,997,1001,1005,1009,1013,1017,1021,1025,1029,1033,1037,1041,
1045,1049,1053,1057,1061,1065,1069,1073,1077,1081,1085,1089,1093,1097,1101,
1105, 1109, 1113, 1117, 1121, 1125, 1129, 1133, 1137, 1141, 1145, 1149, 1153,
1157, 1161,
1165, 1169, 1173, 1177, 1181, 1185, 1189, 1193, 1197, 1361, 1363, 1365, 1367,
1369, 1371,
1373, and 1375 and a heavy chain comprising a sequence selected from the group
consisting
of SEQ ID NOs: 962, 966, 970, 974, 978, 982, 986, 990, 994, 998, 1002, 1006,
1010, 1014,
1018, 1022, 1026, 1030, 1034, 1038, 1042, 1046, 1050, 1054, 1058, 1062, 1066,
1070, 1074,
1078, 1082, 1086, 1090, 1094, 1098, 1102, 1106, 1110, 1114, 1118, 1122, 1126,
1130, 1134,
1138, 1142, 1146, 1150, 1154, 1158, 1162, 1166, 1170, 1174, 1178, 1182, 1186,
1190, 1194,
1198, 1362, 1364, 1366, 1368, 1370, 1372, 1374, and 1376. In one embodiment
the antibody
or fragment thereof comprises a combination of light chain variable region and
a heavy chain
variable region selected from the group consisting of a light chain encoded by
a
polynucleotide sequence comprising SEQ ID NO: 961 and a heavy chain encoded by
a
polynucleotide sequence comprising SEQ ID NO: 962; a light chain encoded by a
polynucleotide sequence comprising SEQ ID NO: 965 and a heavy chain encoded by
a
polynucleotide sequence comprising SEQ ID NO: 966; a light chain encoded by a
polynucleotide sequence comprising SEQ ID NO: 969 and a heavy chain encoded by
a
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polynucleotide sequence comprising SEQ ID NO: 970; a light chain encoded by a
polynucleotide sequence comprising SEQ ID NO: 973 and a heavy chain encoded by
a
polynucleotide sequence comprising SEQ ID NO: 974; a light chain encoded by a
polynucleotide sequence comprising SEQ ID NO: 977 and a heavy chain encoded by
a
polynucleotide sequence comprising SEQ ID NO: 978; a light chain encoded by a
polynucleotide sequence comprising SEQ ID NO: 981 and a heavy chain encoded by
a
polynucleotide sequence comprising SEQ ID NO: 982; a light chain encoded by a
polynucleotide sequence comprising SEQ ID NO: 985 and a heavy chain encoded by
a
polynucleotide sequence comprising SEQ ID NO: 986; a light chain encoded by a
polynucleotide sequence comprising SEQ ID NO: 989 and a heavy chain encoded by
a
polynucleotide sequence comprising SEQ ID NO: 990; a light chain encoded by a
polynucleotide sequence comprising SEQ ID NO: 993 and a heavy chain encoded by
a
polynucleotide sequence comprising SEQ ID NO: 994; a light chain encoded by a
polynucleotide sequence comprising SEQ ID NO: 997 and a heavy chain encoded by
a
polynucleotide sequence comprising SEQ ID NO: 998; a light chain encoded by a
polynucleotide sequence comprising SEQ ID NO: 1001 and a heavy chain encoded
by a
polynucleotide sequence comprising SEQ ID NO: 1002; a light chain encoded by a
polynucleotide sequence comprising SEQ ID NO: 1005 and a heavy chain encoded
by a
polynucleotide sequence comprising SEQ ID NO: 1006; a light chain encoded by a
polynucleotide sequence comprising SEQ ID NO: 1009 and a heavy chain encoded
by a
polynucleotide sequence comprising SEQ ID NO: 1010; a light chain encoded by a
polynucleotide sequence comprising SEQ ID NO: 1013 and a heavy chain encoded
by a
polynucleotide sequence comprising SEQ ID NO: 1014; a light chain encoded by a
polynucleotide sequence comprising SEQ ID NO: 1017 and a heavy chain encoded
by a
polynucleotide sequence comprising SEQ ID NO: 1018; alight chain encoded by a
polynucleotide sequence comprising SEQ ID NO: 1021 and a heavy chain encoded
by a
polynucleotide sequence comprising SEQ ID NO: 1022; a light chain encoded by a
polynucleotide sequence comprising SEQ ID NO: 1025 and a heavy chain encoded
by a
polynucleotide sequence comprising SEQ ID NO: 1026; a light chain encoded by a
polynucleotide sequence comprising SEQ ID NO: 1029 and a heavy chain encoded
by a
polynucleotide sequence comprising SEQ ID NO: 1030; a light chain encoded by a
polynucleotide sequence comprising SEQ ID NO: 1033 and a heavy chain encoded
by a
polynucleotide sequence comprising SEQ ID NO: 1034; a light chain encoded by a
polynucleotide sequence comprising SEQ ID NO: 1037 and a heavy chain encoded
by a
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polynucleotide sequence comprising SEQ ID NO: 1038; a light chain encoded by a
polynucleotide sequence comprising SEQ ID NO: 1041 and a heavy chain encoded
by a
polynucleotide sequence comprising SEQ ID NO: 1042; a light chain encoded by a
polynucleotide sequence comprising SEQ ID NO: 1045 and a heavy chain encoded
by a
polynucleotide sequence comprising SEQ ID NO: 1046; a light chain encoded by a
polynucleotide sequence comprising SEQ ID NO: 1049 and a heavy chain encoded
by a
polynucleotide sequence comprising SEQ ID NO: 1050; a light chain encoded by a
polynucleotide sequence comprising SEQ ID NO: 1053 and a heavy chain encoded
by a
polynucleotide sequence comprising SEQ ID NO: 1054; a light chain encoded by a
polynucleotide sequence comprising SEQ ID NO: 1057 and a heavy chain encoded
by a
polynucleotide sequence comprising SEQ ID NO: 1058; a light chain encoded by a
polynucleotide sequence comprising SEQ ID NO: 1061 and a heavy chain encoded
by a
polynucleotide sequence comprising SEQ ID NO: 1062; a light chain encoded by a
polynucleotide sequence comprising SEQ ID NO: 1065 and a heavy chain encoded
by a
polynucleotide sequence comprising SEQ ID NO: 1066; a light chain encoded by a
polynucleotide sequence comprising SEQ ID NO: 1069 and a heavy chain encoded
by a
polynucleotide sequence comprising SEQ ID NO: 1070; a light chain encoded by a
polynucleotide sequence comprising SEQ ID NO: 1073 and a heavy chain encoded
by a
polynucleotide sequence comprising SEQ ID NO: 1074; a light chain encoded by a
polynucleotide sequence comprising SEQ ID NO: 1077 and a heavy chain encoded
by a
polynucleotide sequence comprising SEQ ID NO: 1078; a light chain encoded by a
polynucleotide sequence comprising SEQ ID NO: 1081 and a heavy chain encoded
by a
polynucleotide sequence comprising SEQ ID NO: 1082; a light chain encoded by a
polynucleotide sequence comprising SEQ ID NO: 1085 and a heavy chain encoded
by a
polynucleotide sequence comprising SEQ ID NO: 1086; a light chain encoded by a
polynucleotide sequence comprising SEQ ID NO: 1089 and a heavy chain encoded
by a
polynucleotide sequence comprising SEQ ID NO: 1090; a light chain encoded by a
polynucleotide sequence comprising SEQ ID NO: 1093 and a heavy chain encoded
by a
polynucleotide sequence comprising SEQ ID NO: 1094; a light chain encoded by a
polynucleotide sequence comprising SEQ ID NO: 1097 and a heavy chain encoded
by a
polynucleotide sequence comprising SEQ ID NO: 1098; a light chain encoded by a
polynucleotide sequence comprising SEQ ID NO: 1101 and a heavy chain encoded
by a
polynucleotide sequence comprising SEQ ID NO: 1102; a light chain encoded by a
polynucleotide sequence comprising SEQ ID NO: 1105 and a heavy chain encoded
by a
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polynucleotide sequence comprising SEQ ID NO: 1106; a light chain encoded by a
polynucleotide sequence comprising SEQ ID NO: 1109 and a heavy chain encoded
by a
polynucleotide sequence comprising SEQ ID NO: 1110; a light chain encoded by a
polynucleotide sequence comprising SEQ ID NO: 1113 and a heavy chain encoded
by a
polynucleotide sequence comprising SEQ ID NO: 1114; a light chain encoded by a
polynucleotide sequence comprising SEQ ID NO: 1117 and a heavy chain encoded
by a
polynucleotide sequence comprising SEQ ID NO: 1118; a light chain encoded by a
polynucleotide sequence comprising SEQ ID NO: 1121 and a heavy chain encoded
by a
polynucleotide sequence comprising SEQ ID NO: 1122; a light chain encoded by a
polynucleotide sequence comprising SEQ ID NO: 1125 and a heavy chain encoded
by a
polynucleotide sequence comprising SEQ ID NO: 1126; a light chain encoded by a
polynucleotide sequence comprising SEQ ID NO: 1129 and a heavy chain encoded
by a
polynucleotide sequence comprising SEQ ID NO: 1130; a light chain encoded by a
polynucleotide sequence comprising SEQ ID NO: 1133 and a heavy chain encoded
by a
polynucleotide sequence comprising SEQ ID NO: 1134; a light chain encoded by a
polynucleotide sequence comprising SEQ ID NO: 1137 and a heavy chain encoded
by a
polynucleotide sequence comprising SEQ ID NO: 1138; a light chain encoded by a
polynucleotide sequence comprising SEQ ID NO: 1141 and a heavy chain encoded
by a
polynucleotide sequence comprising SEQ ID NO: 1142; a light chain encoded by a
polynucleotide sequence comprising SEQ ID NO: 1145 and a heavy chain encoded
by a
polynucleotide sequence comprising SEQ ID NO: 1146; a light chain encoded by a
polynucleotide sequence comprising SEQ ID NO: 1149 and a heavy chain encoded
by a
polynucleotide sequence comprising SEQ ID NO: 1150; a light chain encoded by a
polynucleotide sequence comprising SEQ ID NO: 1153 and a heavy chain encoded
by a
polynucleotide sequence comprising SEQ ID NO: 1154; a light chain encoded by a
polynucleotide sequence comprising SEQ ID NO: 1157 and a heavy chain encoded
by a
polynucleotide sequence comprising SEQ ID NO: 1158; a light chain encoded by a
polynucleotide sequence comprising SEQ ID NO: 1161 and a heavy chain encoded
by a
polynucleotide sequence comprising SEQ ID NO: 1162; a light chain encoded by a
polynucleotide sequence comprising SEQ ID NO: 1165 and a heavy chain encoded
by a
polynucleotide sequence comprising SEQ ID NO: 1166; a light chain encoded by a
polynucleotide sequence comprising SEQ ID NO: 1169 and a heavy chain encoded
by a
polynucleotide sequence comprising SEQ ID NO: 1170; a light chain encoded by a
polynucleotide sequence comprising SEQ ID NO: 1173 and a heavy chain encoded
by a
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polynucleotide sequence comprising SEQ ID NO: 1174; a light chain encoded by a
polynucleotide sequence comprising SEQ ID NO: 1177 and a heavy chain encoded
by a
polynucleotide sequence comprising SEQ ID NO: 1178; a light chain encoded by a
polynucleotide sequence comprising SEQ ID NO: 1181 and a heavy chain encoded
by a
polynucleotide sequence comprising SEQ ID NO: 1182; a light chain encoded by a
polynucleotide sequence comprising SEQ ID NO: 1185 and a heavy chain encoded
by a
polynucleotide sequence comprising SEQ ID NO: 1186; a light chain encoded by a
polynucleotide sequence comprising SEQ ID NO: 1189 and a heavy chain encoded
by a
polynucleotide sequence comprising SEQ ID NO: 1190; a light chain encoded by a
polynucleotide sequence comprising SEQ ID NO: 1193 and a heavy chain encoded
by a
polynucleotide sequence comprising SEQ ID NO: 1194; a light chain encoded by a
polynucleotide sequence comprising SEQ ID NO: 1197 and a heavy chain encoded
by a
polynucleotide sequence comprising SEQ ID NO: 1198; a light chain encoded by a
polynucleotide sequence comprising SEQ ID NO: 1361 and a heavy chain encoded
by a
polynucleotide sequence comprising SEQ ID NO: 1362; a light chain encoded by a
polynucleotide sequence comprising SEQ ID NO: 1363 and a heavy chain encoded
by a
polynucleotide sequence comprising SEQ ID NO: 1364; a light chain encoded by a
polynucleotide sequence comprising SEQ ID NO: 1365 and a heavy chain encoded
by a
polynucleotide sequence comprising SEQ ID NO: 1366; a light chain encoded by a
polynucleotide sequence comprising SEQ ID NO: 1367 and a heavy chain encoded
by a
polynucleotide sequence comprising SEQ ID NO: 1368; a light chain encoded by a
polynucleotide sequence comprising SEQ ID NO: 1369 and a heavy chain encoded
by a
polynucleotide sequence comprising SEQ ID NO: 1370; a light chain encoded by a
polynucleotide sequence comprising SEQ ID NO: 1371 and a heavy chain encoded
by a
polynucleotide sequence comprising SEQ ID NO: 1372; a light chain encoded by a
polynucleotide sequence comprising SEQ ID NO: 1373 and a heavy chain encoded
by a
polynucleotide sequence comprising SEQ ID NO: 1374; and a light chain encoded
by a
polynucleotide sequence comprising SEQ ID NO: 1375 and a heavy chain encoded
by a
polynucleotide sequence comprising SEQ ID NO: 1376.
[0229] In some aspects, the invention comprises an antibody that binds to
GIPR, wherein the
antibody binds to GIPR and reduces the likelihood that GIPR binds to GIP.
[0230] In another aspect, the antigen binding protein comprises a full length
light chain and a
full length heavy chain as listed in one of the rows for one of the antibodies
listed in TABLE
5. Some antigen binding proteins that are provided comprise a full length
light chain and a
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full length heavy chain as listed in one of the rows for one of the antibodies
listed in TABLE
5, except that one or both of the chains differs from the sequence specified
in the table at only
1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid residues,
wherein each such
sequence difference is independently either a single amino acid deletion,
insertion or
substitution, with the deletions, insertions and/or substitutions resulting in
no more than 1, 2,
3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid changes relative to
the full length
sequences specified in TABLE 5. In one embodiment the antigen binding protein
comprises a
full length light chain and/or a full length heavy chain from Table 5 with the
N-terminal
methionine deleted. In one embodiment the antigen binding protein comprises a
full length
light chain and/or a full length heavy chain from Table 5 with the C-terminal
lysine deleted.
Other antigen binding proteins also comprise a full length light chain and a
full length heavy
chain as listed in one of the rows for one of the antibodies listed in TABLE
5, except that one
or both of the chains differs from the sequence specified in the table in that
the light chain
and/or heavy chain comprises or consists of a sequence of amino acids that has
at least 70%,
75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino
acid
sequences of the light chain or heavy chain sequences as specified in TABLE S.
[0231] In another embodiment, the antigen binding protein consists of a just a
light or a
heavy chain polypeptide as set forth in TABLE S.
[0232] In still another aspect, antigen-binding proteins containing the CDRs,
variable
domains and/or full length sequences listed in TABLES 3, 4A, 4B, and 5 is a
monoclonal
antibody, a chimeric antibody, a humanized antibody, a human antibody, a
multispecific
antibody, or an antibody fragment of the foregoing. In another embodiment, the
antibody
fragment of the isolated antigen-binding proteins provided herein is a Fab
fragment, a Fab'
fragment, an F(ab1)2 fragment, an Fv fragment, a diabody, or a scFv based upon
an antibody
with the sequences as listed in TABLE S.
[0233] In yet another aspect, the isolated antigen-binding protein provided in
TABLE 5 can
be coupled to a labeling group and can compete for binding to GIPR with an
antigen binding
protein of one of the isolated antigen-binding proteins provided herein.
[0234] In another embodiment, antigen binding proteins are provided that
compete with one
of the exemplified antibodies or functional fragments described above for
specific binding to
a human GIPR (e.g., SEQ ID NO: 1201). Such antigen binding proteins may bind
to the same
epitope as one of the antigen binding proteins described herein, or to an
overlapping epitope.
Antigen binding proteins and fragments that compete with the exemplified
antigen binding
proteins are expected to show similar functional properties. The exemplified
antigen binding
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proteins and fragments include those described above, including those with
heavy and light
chains, variable region domains and CDRs included in TABLES 3, 4A, 4B, and 5.
Thus, as a
specific example, the antigen binding proteins that are provided include those
that compete
with an antibody having:
[0235] all 6 of the CDRs listed for any antibody listed in TABLES 4A and 4B;
[0236] a VH and a VL listed for any antibody listed in TABLE 3; or
[0237] two light chains and two heavy chains as specified for any antibody
listed in TABLE
5.
[0238] The antigen binding proteins that are provided include monoclonal
antibodies that
bind to GIPR. Monoclonal antibodies may be produced using any technique known
in the art,
e.g., by immortalizing spleen cells harvested from the transgenic animal after
completion of
the immunization schedule. The spleen cells can be immortalized using any
technique known
in the art, e.g., by fusing them with myeloma cells to produce hybridomas.
Myeloma cells for
use in hybridoma-producing fusion procedures preferably are non-antibody-
producing, have
high fusion efficiency, and enzyme deficiencies that render them incapable of
growing in
certain selective media which support the growth of only the desired fused
cells
(hybridomas). Examples of suitable cell lines for use in mouse fusions include
Sp-20, P3-
X63/Ag8, P3-X63-Ag8.653, NS1/1.Ag 4 1, 5p210-Ag14, FO, NSO/U, MPC-11, MPC11-
X45-GTG 1.7 and 5194/5XXO Bul; examples of cell lines used in rat fusions
include
R210.RCY3, Y3-Ag 1.2.3, IR983F and 4B210. Other cell lines useful for cell
fusions are U-
266, GM1500-GRG2, LICR-LON-HMy2 and UC729-6.
[0239] In some instances, a hybridoma cell line is produced by immunizing an
animal (e.g., a
transgenic animal having human immunoglobulin sequences) with a GIPR
immunogen;
harvesting spleen cells from the immunized animal; fusing the harvested spleen
cells to a
myeloma cell line, thereby generating hybridoma cells; establishing hybridoma
cell lines
from the hybridoma cells, and identifying a hybridoma cell line that produces
an antibody
that binds a GIPR polypeptide. Such hybridoma cell lines, and anti-GIPR
monoclonal
antibodies produced by them, are aspects of the present application.
[0240] Monoclonal antibodies secreted by a hybridoma cell line can be purified
using any
technique known in the art. Hybridomas or mAbs may be further screened to
identify mAbs
with particular properties, such as the ability to increase GIPR activity.
[0241] Chimeric and humanized antibodies based upon the foregoing sequences
are also
provided. Monoclonal antibodies for use as therapeutic agents may be modified
in various
ways prior to use. One example is a chimeric antibody, which is an antibody
composed of
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protein segments from different antibodies that are covalently joined to
produce functional
immunoglobulin light or heavy chains or immunologically functional portions
thereof
Generally, a portion of the heavy chain and/or light chain is identical with
or homologous to a
corresponding sequence in antibodies derived from a particular species or
belonging to a
particular antibody class or subclass, while the remainder of the chain(s)
is/are identical with
or homologous to a corresponding sequence in antibodies derived from another
species or
belonging to another antibody class or subclass. For methods relating to
chimeric antibodies,
see, for example, United States Patent No. 4,816,567; and Morrison etal.,
1985, Proc. Natl.
Acad. Sci. USA 81:6851-6855, which are hereby incorporated by reference. CDR
grafting is
described, for example, in United States Patent No. 6,180,370, No. 5,693,762,
No. 5,693,761,
No. 5,585,089, and No. 5,530,101.
[0242] Generally, the goal of making a chimeric antibody is to create a
chimera in which the
number of amino acids from the intended patient species is maximized. One
example is the
"CDR-grafted" antibody, in which the antibody comprises one or more
complementarity
determining regions (CDRs) from a particular species or belonging to a
particular antibody
class or subclass, while the remainder of the antibody chain(s) is/are
identical with or
homologous to a corresponding sequence in antibodies derived from another
species or
belonging to another antibody class or subclass. For use in humans, the
variable region or
selected CDRs from a rodent antibody often are grafted into a human antibody,
replacing the
naturally-occurring variable regions or CDRs of the human antibody.
[0243] One useful type of chimeric antibody is a "humanized" antibody.
Generally, a
humanized antibody is produced from a monoclonal antibody raised initially in
a non-human
animal. Certain amino acid residues in this monoclonal antibody, typically
from non-antigen
recognizing portions of the antibody, are modified to be homologous to
corresponding
residues in a human antibody of corresponding isotype. Humanization can be
performed, for
example, using various methods by substituting at least a portion of a rodent
variable region
for the corresponding regions of a human antibody (see, e.g., United States
Patent No.
5,585,089, and No. 5,693,762; Jones etal., 1986, Nature 321:522-525; Riechmann
etal.,
1988, Nature 332:323-27; Verhoeyen etal., 1988, Science 239:1534-1536).
[0244] In one aspect, the CDRs of the light and heavy chain variable regions
of the
antibodies provided herein are grafted to framework regions (FRs) from
antibodies from the
same, or a different, phylogenetic species. For example, the CDRs of the heavy
and light
chain variable regions VH1, VH2, VH3, VH4, VHS, VH6, VH7, VH8, VH9, VH10,
VH11, VH12
and/or VL1, and VL2 can be grafted to consensus human FRs. To create consensus
human
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FRs, FRs from several human heavy chain or light chain amino acid sequences
may be
aligned to identify a consensus amino acid sequence. In other embodiments, the
FRs of a
heavy chain or light chain disclosed herein are replaced with the FRs from a
different heavy
chain or light chain. In one aspect, rare amino acids in the FRs of the heavy
and light chains
of GIPR antibodies are not replaced, while the rest of the FR amino acids are
replaced. A
"rare amino acid" is a specific amino acid that is in a position in which this
particular amino
acid is not usually found in an FR. Alternatively, the grafted variable
regions from the one
heavy or light chain may be used with a constant region that is different from
the constant
region of that particular heavy or light chain as disclosed herein. In other
embodiments, the
grafted variable regions are part of a single chain FAT antibody.
[0245] In certain embodiments, constant regions from species other than human
can be used
along with the human variable region(s) to produce hybrid antibodies.
[0246] Fully human GIPR antibodies are also provided. Methods are available
for making
fully human antibodies specific for a given antigen without exposing human
beings to the
antigen ("fully human antibodies"). One specific means provided for
implementing the
production of fully human antibodies is the "humanization" of the mouse
humoral immune
system. Introduction of human immunoglobulin (Ig) loci into mice in which the
endogenous
Ig genes have been inactivated is one means of producing fully human
monoclonal antibodies
(mAbs) in mouse, an animal that can be immunized with any desirable antigen.
Using fully
human antibodies can minimize the immunogenic and allergic responses that can
sometimes
be caused by administering mouse or mouse-derived mAbs to humans as
therapeutic agents.
[0247] Fully human antibodies can be produced by immunizing transgenic animals
(usually
mice) that are capable of producing a repertoire of human antibodies in the
absence of
endogenous immunoglobulin production. Antigens for this purpose typically have
six or more
contiguous amino acids, and optionally are conjugated to a carrier, such as a
hapten. See, e.g.,
Jakobovits etal., 1993, Proc. Natl. Acad. Sci. USA 90:2551-2555; Jakobovits
etal., 1993,
Nature 362:255-258; and Bruggermann etal., 1993, Year in Immunol. 7:33. In one
example
of such a method, transgenic animals are produced by incapacitating the
endogenous mouse
immunoglobulin loci encoding the mouse heavy and light immunoglobulin chains
therein,
and inserting into the mouse genome large fragments of human genome DNA
containing loci
that encode human heavy and light chain proteins. Partially modified animals,
which have
less than the full complement of human immunoglobulin loci, are then cross-
bred to obtain an
animal having all of the desired immune system modifications. When
administered an
immunogen, these transgenic animals produce antibodies that are immunospecific
for the
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immunogen but have human rather than murine amino acid sequences, including
the variable
regions. For further details of such methods, see, for example, W096/33735 and
W094/02602. Additional methods relating to transgenic mice for making human
antibodies
are described in United States Patent No. 5,545,807; No. 6,713,610; No.
6,673,986;
No. 6,162,963; No. 5,545,807; No. 6,300,129; No. 6,255,458; No. 5,877,397; No.
5,874,299
and No. 5,545,806; in PCT publications W091/10741, W090/04036, and in EP
546073B1
and EP 546073A1.
[0248] The transgenic mice described above, referred to herein as "HuMab"
mice, contain a
human immunoglobulin gene minilocus that encodes unrearranged human heavy
([mu] and
[gamma]) and [kappa] light chain immunoglobulin sequences, together with
targeted
mutations that inactivate the endogenous [mu] and [kappa] chain loci (Lonberg
et al., 1994,
Nature 368:856-859). Accordingly, the mice exhibit reduced expression of mouse
IgM or
[kappa] and in response to immunization, and the introduced human heavy and
light chain
transgenes undergo class switching and somatic mutation to generate high
affinity human IgG
[kappa] monoclonal antibodies (Lonberg etal., supra.; Lonberg and Huszar,
1995, Intern.
Rev. Immunol. 13: 65-93; Harding and Lonberg, 1995, Ann. NY Acad. Sci. 764:536-
546).
The preparation of HuMab mice is described in detail in Taylor et al., 1992,
Nucleic Acids
Research 20:6287-6295; Chen etal., 1993, International Immunology 5:647-656;
Tuaillon et
al., 1994,1 Immunol. 152:2912-2920; Lonberg etal., 1994, Nature 368:856-859;
Lonberg,
1994, Handbook of Exp. Pharmacology 113:49-101; Taylor etal., 1994,
International
Immunology 6:579-591; Lonberg and Huszar, 1995, Intern. Rev. Immunol. 13:65-
93; Harding
and Lonberg, 1995, Ann. NY Acad. Sci. 764:536-546; Fishwild etal., 1996,
Nature
Biotechnology 14:845-851; the foregoing references are hereby incorporated by
reference in
their entirety for all purposes. See, further United States Patent No.
5,545,806; No. 5,569,825;
No. 5,625,126; No. 5,633,425; No. 5,789,650; No. 5,877,397; No. 5,661,016; No.
5,814,318;
No. 5,874,299; and No. 5,770,429; as well as United States Patent No.
5,545,807;
International Publication Nos. WO 93/1227; WO 92/22646; and WO 92/03918, the
disclosures of all of which are hereby incorporated by reference in their
entirety for all
purposes. Technologies utilized for producing human antibodies in these
transgenic mice are
disclosed also in WO 98/24893, and Mendez etal., 1997, Nature Genetics 15:146-
156, which
are hereby incorporated by reference. For example, the HCo7 and HCo12
transgenic mice
strains can be used to generate human monoclonal antibodies against GIPR.
Further details
regarding the production of human antibodies using transgenic mice are
provided below.
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[0249] Using hybridoma technology, antigen-specific human mAbs with the
desired
specificity can be produced and selected from the transgenic mice such as
those described
above. Such antibodies may be cloned and expressed using a suitable vector and
host cell, or
the antibodies can be harvested from cultured hybridoma cells.
[0250] Fully human antibodies can also be derived from phage-display libraries
(as disclosed
in Hoogenboom etal., 1991, 1 Mol. Biol. 227:381; and Marks et al., 1991, 1
Mol. Biol.
222:581). Phage display techniques mimic immune selection through the display
of antibody
repertoires on the surface of filamentous bacteriophage, and subsequent
selection of phage by
their binding to an antigen of choice. One such technique is described in PCT
Publication No.
WO 99/10494 (hereby incorporated by reference).
[0251] The GIPR binding protein can also be a variant, mimetic, derivative or
oligomer
based upon the structure of GIPR antigen binding proteins have the CDRs,
variable regions
and/or full length chains as described above.
[0252] In one embodiment, for instance, an antigen binding protein is a
variant form of the
antigen binding proteins disclosed above. For instance, some of the antigen
binding proteins
have one or more conservative amino acid substitutions in one or more of the
heavy or light
chains, variable regions or CDRs.
[0253] Naturally-occurring amino acids may be divided into classes based on
common side
chain properties:
[0254] 1) hydrophobic: norleucine, Met, Ala, Val, Leu, Ile;
[0255] 2) neutral hydrophilic: Cys, Ser, Thr, Asn, Gln;
[0256] 3) acidic: Asp, Glu;
[0257] 4) basic: His, Lys, Arg;
[0258] 5) residues that influence chain orientation: Gly, Pro; and
[0259] 6) aromatic: Trp, Tyr, Phe.
[0260] Conservative amino acid substitutions may involve exchange of a member
of one of
these classes with another member of the same class. Conservative amino acid
substitutions
may encompass non-naturally occurring amino acid residues, which are typically
incorporated by chemical peptide synthesis rather than by synthesis in
biological systems.
These include peptidomimetics and other reversed or inverted forms of amino
acid moieties.
[0261] Non-conservative substitutions may involve the exchange of a member of
one of the
above classes for a member from another class. Such substituted residues may
be introduced
into regions of the antibody that are homologous with human antibodies, or
into the non-
homologous regions of the molecule.
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[0262] In making such changes, according to certain embodiments, the
hydropathic index of
amino acids may be considered. The hydropathic profile of a protein is
calculated by
assigning each amino acid a numerical value ("hydropathy index") and then
repetitively
averaging these values along the peptide chain. Each amino acid has been
assigned a
hydropathic index on the basis of its hydrophobicity and charge
characteristics. They are:
isoleucine (+4.5); valine (+4.2); leucine (+3.8); phenylalanine (+2.8);
cysteine/cystine (+2.5);
methionine (+1.9); alanine (+1.8); glycine (-0.4); threonine (-0.7); serine (-
0.8); tryptophan (-
0.9); tyrosine (-1.3); proline (-1.6); histidine (-3.2); glutamate (-3.5);
glutamine (-3.5);
aspartate (-3.5); asparagine (-3.5); lysine (-3.9); and arginine (-4.5).
[0263] The importance of the hydropathic profile in conferring interactive
biological function
on a protein is understood in the art (see, e.g., Kyte et al., 1982, 1 Mol.
Biol. 157:105-131). It
is known that certain amino acids may be substituted for other amino acids
having a similar
hydropathic index or score and still retain a similar biological activity. In
making changes
based upon the hydropathic index, in certain embodiments, the substitution of
amino acids
whose hydropathic indices are within 2 is included. In some aspects, those
which are within
1 are included, and in other aspects, those within 0.5 are included.
[0264] It is also understood in the art that the substitution of like amino
acids can be made
effectively on the basis of hydrophilicity, particularly where the
biologically functional
protein or peptide thereby created is intended for use in immunological
embodiments, as in
the present case. In certain embodiments, the greatest local average
hydrophilicity of a
protein, as governed by the hydrophilicity of its adjacent amino acids,
correlates with its
immunogenicity and antigen-binding or immunogenicity, that is, with a
biological property of
the protein.
[0265] The following hydrophilicity values have been assigned to these amino
acid residues:
arginine (+3.0); lysine (+3.0); aspartate (+3.0 1); glutamate (+3.0 1); serine
(+0.3);
asparagine (+0.2); glutamine (+0.2); glycine (0); threonine (-0.4); proline (-
0.5 1); alanine (-
0.5); histidine (-0.5); cysteine (-1.0); methionine (-1.3); valine (-1.5);
leucine (-1.8);
isoleucine (-1.8); tyrosine (-2.3); phenylalanine (-2.5) and tryptophan (-
3.4). In making
changes based upon similar hydrophilicity values, in certain embodiments, the
substitution of
amino acids whose hydrophilicity values are within 2 is included, in other
embodiments,
those which are within 1 are included, and in still other embodiments, those
within 0.5 are
included. In some instances, one may also identify epitopes from primary amino
acid
sequences on the basis of hydrophilicity. These regions are also referred to
as "epitopic
core regions."
222
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WO 2018/237097
PCT/US2018/038638
[0266] Exemplary conservative amino acid substitutions are set forth in Table
6.
Table 8: Conservative Amino Acid Substitutions
Original Residue Exemplary Substitutions
Ala Ser
Arg Lys
Asn Gln, His
Asp Glu
Cys Ser
Gln Asn
Glu Asp
Gly Pro
His Asn, Gln
Ile Leu, Val
Leu Ile, Val
Lys Arg, Gln, Glu
Met Leu, Ile
Phe Met, Leu, Tyr
Ser Thr
Thr Ser
Trp Tyr
Tyr Trp, Phe
Val Ile, Leu
[0267] A skilled artisan will be able to determine suitable variants of
polypeptides as set forth
herein using well-known techniques. One skilled in the art may identify
suitable areas of the
molecule that may be changed without destroying activity by targeting regions
not believed
to be important for activity. The skilled artisan also will be able to
identify residues and
portions of the molecules that are conserved among similar polypeptides. In
further
embodiments, even areas that may be important for biological activity or for
structure may be
subject to conservative amino acid substitutions without destroying the
biological activity or
without adversely affecting the polypeptide structure.
[0268] Additionally, one skilled in the art can review structure-function
studies identifying
residues in similar polypeptides that are important for activity or structure.
In view of such a
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